Managing HER2+ Early Breast Cancer: Insights and Future Horizons

In this Precision Medicine Perspectives series Navigating HER2+ Early Breast Cancer: Insights, Innovations, and Future Horizons, Sandra M. Swain, MD, associate dean for research development and professor of medicine at the Georgetown University Medical Cancer, offers a an overview of available data on HER2-directed tyrosine kinase inhibitors (TKIs) and discusses how emerging data on potential treatment regimens for early-stage HER2-positive (HER2+) breast cancer.

Targeted Oncology™: Please discuss the role of HER2-directed TKIs. Which patients would you consider for this treatment?

Dr Swain: TKIs, including lapatinib, have been tested in the adjuvant setting and are not as effective as the monoclonal antibodies trastuzumab and pertuzumab. Currently, we don’t use [these TKIs] at all in the neoadjuvant or adjuvant setting. However, 1 TKI that has been used is neratinib. This agent was used in a study called the ExteNET trial (NCT00878709). It was a randomized, double blind, placebo-controlled, phase 3 trial in women who had either stage I or up to [stage] III breast cancer who had already completed their neoadjuvant and adjuvant chemotherapy with trastuzumab but had no evidence of disease recurrence. Patients enrolled were [randomly assigned] to either neratinib or placebo. In this study, the reported results were that the invasive disease-free survival was significantly better in those patients who got the neratinib, showing improvement by approximately 2%. Additionally, the time to distant disease recurrence was improved, [al]though it wasn’t significant. What’s interesting about the use of neratinib was that pertuzumab was not used in any of these patients as it was many years ago, and T-DM1 [trastuzumab emtansine] was not used for those residual-disease tumors.

Looking at the data from the ExteNET trial, those patients who had 4 or more positive nodes seem to have the best benefit from the use of neratinib with a hazard ratio of 0.67. Also, in those patients who had hormone receptor–positive tumors, the hazard ratio was 0.60. The thinking now is that if you’re going to recommend neratinib, it would be for those patients who are [at] high risk for recurrence after T-DM1 and who have hormone receptor–positive tumors with the caveat that [this patient population was not looked at in the ExteNET trial as the patients were not treated with] T-DM1 or pertuzumab. It’s really the physician's choice of how to deal with that, because we don’t have real data there.

A concern with neratinib is that high levels of diarrhea were demonstrated in the ExteNET study. In the first publication [of the results], about 95% to 96% of patients had diarrhea, and 40% [of those patients had] grade 3 diarrhea compared to 2% in the placebo group. So, that's really a toxicity [that makes it] difficult for patients who essentially could be cured with just the use of trastuzumab, pertuzumab, and T-DM1. That really needs to be taken into consideration when using this drug. I think, looking at the data from the CONTROL study (NCT02400476), that they did try [to] decrease the amount of diarrhea, [and that] is important. The CONTROL study [investigators] used several different strategies to try to decrease diarrhea, including starting at a lower dose and dose escalation. If I were to use it, it would only be in that setting where I would start low and increase the dose slowly to make sure that the quality of life for a patient was good.

Targeted Oncology: Looking at the future treatment landscape, what emerging research do you find most impactful and exciting?

Dr Swain: What's exciting right now is the new antibody-drug conjugates like trastuzumab deruxtecan (T-DXd), which is really incredibly active compared to T-DM1. T-DXd demonstrates a huge clinical benefit, with a hazard ratio of 0.28. I don't think we’ve seen a curve like that ever in breast cancer, and that was for patients in the second line comparing T-DXd to T-DM1. Now, it is the standard second-line metastatic treatment.

Due to its high activity, trastuzumab deruxtecan has been studied in [the] first line in clinical trials, such as the DESTINY-Breast09 trial (NCT04784715), for example. Additionally, the DESTINY-Breast11 study (NCT05113251), which has completed accrual, is a neoadjuvant study looking at T-DXd either as monotherapy or T-DXd followed by THP (paclitaxel plus trastuzumab plus pertuzumab) compared to a standard regimen [dose-dense doxorubicin plus cyclophosphamide followed by THP]. This is in patients with node-positive disease or with the primary tumor stage 3 and 4, locally advanced or inflammatory, HER2+ early-stage breast cancer. This study has completed accrual, and we’re anxiously awaiting to see if that will actually change the standard of treatment in the neoadjuvant setting. The primary end point for this trial is pCR [pathologic complete response], but hopefully it will translate into an overall survival benefit as it has in the metastatic setting. I’m very excited about that. Also, the DESTINY-Breast05 study (NCT04622319) is looking at T-DXd neoadjuvant, comparing the T-DXd to T-DM1, and that is probably going to complete accrual by the end of this year.

The other important topic is looking at biomarkers of efficacy. For example, we may not need to use the carboplatin in the neoadjuvant setting or some of these aggressive new adjuvant regimens. [Results of] some of the German studies have shown, for example, that just using paclitaxel with trastuzumab or pertuzumab [is] as effective. As a result, you don’t really need to use much chemotherapy. Ultimately, we’re trying to optimize the treatment regimens [by] looking for biomarkers that will tell us [which patients are responding to treatment]. One [tool] is the HER2DX assay, which in Europe has been utilized in several studies trying to predict which patients in the neoadjuvant setting will have a pCR. Other [evaluation tools] currently being studied include [fluorine Fl 18–fluorodeoxyglucose] PET imaging in the PHERGain study (NCT03161353), [which used early metabolic evaluation with PET imaging to identify which patients had the best chance of achieving pCR]. [Identifying biomarkers] such as PIK3CA mutations and other immune profiles may help us choose which patients need less therapy and which patients need more.