ADCs, TKIs, and More Expand Treatment Options in HER2+ Metastatic Breast Cancer

With more therapies being added to the armamentarium for HER2-positive metastatic breast cancer, it is more important than ever to stay abreast with recent data to make the best treatment decision for patients, according to Mark D. Pegram, MD.

“The HER2-positive breast cancer space is fast paced with multiple new drug indications, just in the past year [alone],” says Pegram. “The data emerging from HER2-positive metastatic breast cancer is coming at such a pace that, at every meeting, there are important new updates—some of which could influence clinical practice.”

In an interview with OncLive^®,Pegram, the Suzy Yuan-Huey Hung Endowed Professor of Medical Oncology, an associate dean for clinical research quality at Stanford University School of Medicine, an associate director of clinical research at Stanford Comprehensive Cancer Institute, and medical director of the Stanford Clinical Translational Research Unit at Stanford Medicine, expands on the latest data in HER2-positive metastatic breast cancer.

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

Pegram: There is still a high unmet need [to integrate novel therapies to the treatment paradigm for] HER2-positive metastatic breast cancer. Looking back at the original adjuvant trastuzumab [Herceptin] trials in Europe, North America, and the global Breast Cancer Research Group studies with 3 years of follow-up, they all had outstanding disease-free survival data of approximately 80%, and we declared success. At the 10-year mark, however, all of the trials had about a 25% relapse rate. Moreover, if you look at mortality outcomes in these trials, most of the mortality events were due to metastatic breast cancer.

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

There is also the possibility of using endocrine therapy combined with HER2-targeted therapy [for this patient population.] A number of clinical trials have examined combining both ER- and HER2-targeted therapy, stemming from the EGF30008 [NCT00073528], PERTAIN [NCT01491737], TANDEM [NCT03517540], and ALTERNATIVE trials [NCT01160211]. All of these [trials] were combinations of anti-HER2 and anti-estrogen therapies and were deemed to be successful.

At the 2021 ASCO Annual Meeting, a group of Chinese researchers did a randomized phase 3 trial of endocrine therapy plus trastuzumab vs chemotherapy plus trastuzumab, as a first-line treatment for [this patient population]. Surprisingly, the endocrine therapy-plus-trastuzumab arm fared well, statistically meeting its noninferiority end point in the study design. It was quite remarkable for both progression-free survival and overall survival. However, this is prior to 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 because of comorbidities, such as advanced age, or simply patient preference, but we now have a large data set saying that those patients do well.

[There have also been efforts examining] adding on to the CLEOPATRA regimen for those patients with ER and HER2 expression. The PATINA trial [NCT02947685] will look at the combination of palbociclib [Ibrance] with anti-estrogens during the maintenance phase of a CLEOPATRA-like regimen. The EPIK-B2 trial [NCT04208178] is looking at alpelisib [Piqray] in ER- and HER2-positive patients who also harbor PIK3CA mutations, following a CLEOPATRA-like regimen in the maintenance phase, as well.

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 related, [but they have] different payloads. For example, trastuzumab deruxtecan payload with a significant bystander effect, which may account for 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] prior lines of treatment. Moreover, there was an update at the 2021 ASCO Annual Meeting on anecdotal activity with this agent in patients with HER2-positive breast cancer and brain metastases from the DESTINY-Breast01 clinical trial. Objective responses were documented by RECIST criteria, and those responses tended to be durable for a period of months. This suggests that ADCs may have a role in the future of HER2-positive breast cancerand brain metastases, and dedicated trials in that space are ongoing.

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

There is also an ADC [in development] from Bolt Therapeutics that has an immunologic payload that is a Toll-like receptor 7/8 agonist, which will try to stimulate antitumor immunity with an ADC instead of using a chemotherapy payload.

[Finally, we saw updated results from the] HER2CLIMB trial [NCT02614794] at the 2021 ASCO, Annual Meeting, and their OS data still look robust with long-term follow up.

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

One of the key factors when deciding which effective HER2-targeted therapy to use at any given juncture during the course of metastatic disease is the adverse effect profiles. [We must] explain those to patients, as there may be more than 1 option at any given point in time. We do not want to make [treatment decisions] solely based on efficacy, but rather, efficacy divided by toxicity, or the therapeutic index. It is paramount to try to use these drugs in such a way as to maximize patient quality of life, as well as 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 rare responders. However, those are anecdotal and few and far between. This is still the highest unmet need. We do not have a curative strategy for HER2-positive disease when it metastasizes, and some of that is because half of those patients will develop brain metastases. We need dedicated studies of all the new HER2-targeting agents, specifically in that population, to see which ones will be effective. We have that data for tucatinib already, in the in the form of a randomized phase 3 trial, but we do not have that level of evidence for other HER2-targeted agents yet.

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

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

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