Expert Highlights Latest Advances, Next Steps in HER2+ Breast Cancer

Joanne Mortimer, MD

Data from the phase III KATHERINE trial in early HER2-positive breast cancer and smaller studies in the metastatic setting are shaping modern treatment models and testifying to the prospect of improved prognoses, explained Joanne Mortimer, MD.

“We always talk about how breast cancer has become a chronic disease, and that is certainly true for patients with estrogen receptor (ER)—positive breast cancer, said Mortimer. “It has become truer perhaps in the HER2-positive space in which treatment is so incredibly effective.”

In the phase III KATHERINE trial, patients with residual invasive disease after ≥6 cycles of a taxane-containing chemotherapy, with or without anthracycline, and ≥9 weeks of trastuzumab (Herceptin) were randomized to receive either ado-trastuzumab emtansine (T-DM1; Kadcyla) or trastuzumab. Those randomized to receive T-DM1 were 50% less likely to develop invasive disease compared with those who received another year of trastuzumab.¹

Based on the KATHERINE data, the FDA approved T-DM1 in May 2019 for use as an adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant trastuzumab and chemotherapy.

In the metastatic setting, neratinib (Nerlynx), tucatinib (ONT-380), and lapatinib (Tykerb) are all agents of interest, explained Mortimer. Specifically, tucatinib, which boasted a brain-specific response of 42% when used in combination with trastuzumab and capecitabine in an exploratory analysis of patients with brain metastases enrolled in the phase Ib HER2CLIMB trial (NCT02614794).²

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Mortimer, associate director for Education and Training, Comprehensive Cancer Center, Baum Family Professor in Women’s Cancers, vice chair and professor, Department of Medical Oncology & Therapeutics Research, and director, Women’s Cancer Programs, City of Hope, discussed key facets of treatment for patients with early and metastatic HER2-positive breast cancer.

OncLive: What should be emphasized about the current landscape of early-stage HER2-positive breast cancer?

Mortimer: Within the past 6 months, there has been a change in how we treat patients who have larger tumors and who receive upfront neoadjuvant chemotherapy. Neoadjuvant chemotherapy generally includes the combination of pertuzumab (Perjeta) and trastuzumab. Previously, at the time of surgery, we continued trastuzumab with or without pertuzumab for a full year. With the results of the KATHERINE study that were presented at the 2018 San Antonio Breast Cancer Symposium and published in the New England Journal of Medicine, we learned that the addition of 4 cycles of T-DM1 in women who have residual cancer at the time of surgery is associated with a prolonged disease-free survival. That's an entirely practice-changing treatment.

Following the results of the KATHERINE trial, what is the role of adjuvant therapy with pertuzumab and neratinib?

The challenge right now is figuring out whether there is a role for pertuzumab in the adjuvant setting. The APHINITY trial looked at adjuvant trastuzumab and chemotherapy with or without pertuzumab. Unfortunately, when the study was designed, a large number of those women had negative nodes and therein a favorable outcome. In fact, most women would probably be treated with paclitaxel and trastuzumab right now. There is sort of a bias in terms of who was entered in the trial. The results of the randomized study did not show a significant advantage with the addition of pertuzumab to trastuzumab, except, perhaps, in the subset of patients who had positive lymph nodes. In patients with negative lymph nodes, the addition of pertuzumab is probably not needed in the adjuvant setting.

Is the diarrhea associated with neratinib manageable?

We published the results of [the rate of] diarrhea in the NALA trial, which will be presented at the 2019 ASCO Annual Meeting. In the trial, patients received capecitabine with lapatinib or capecitabine and neratinib. The incidence of diarrhea is very high in patients who received neratinib. However, the study was subsequently amended to include high doses of loperamide (Imodium) at the beginning of treatment. By doing that, the diarrhea was generally manageable. It's interesting that the diarrhea associated with neratinib seems to be worse in the first month and then it tapers down a bit. Overall, neratinib-associated diarrhea is controllable.

The role of neratinib is now in the neoadjuvant setting and in the adjuvant setting for women with positive nodes. The FDA approved neratinib for [use in patients with] hormone receptor (HR)—negative and HR-positive breast cancer. However, at 2 and 5 years, the real advantage is in the subset analysis of the ER-positive patients. Those who took neratinib for a year and those who took it closer to completion of treatment had the greatest advantage. The European Medicines Agency only approved neratinib in the setting of ER-positive breast cancer.

What questions still have to be answered?

One of the issues in HER2-positive breast cancer continues to be brain metastases. Seemingly, brain metastases are more common in patients with HER2-positive disease compared with some of the other subsets.

This continues to be a problem as women live longer with metastatic HER2-positive breast cancer; brain metastases become a component of the metastatic sites. How we treat those women is probably changing. Radiation and surgery are the mainstay of treatment for patients with brain metastases, but often new brain metastases occur in the setting of prior radiation or in places that are inaccessible to radiation and surgery. For those women, there is some evidence that lapatinib has some activity. Neratinib may have some activity as well. T-DM1 has been shown to cause regression of brain metastases in very small series. One of the most promising agents under investigation is tucatinib. The HER2CLIMB study was a randomized trial exploring tucatinib with capecitabine and trastuzumab [or capecitabine and trastuzumab alone]. Tucatinib is so interesting because it is a selective HER2 drug that has been shown to have some activity in preventing and [targeting] brain metastases. This may emerge as a beneficial drug for these women.

Are there other exciting agents being looked at in the metastatic setting?

First-line treatment is very well defined by trastuzumab, pertuzumab, and a taxane. T-DM1 is now the standard of care in the second-line setting. If a patient has not received T-DM1, the guidelines recommend T-DM1 for third-line therapy. Otherwise, it’s an open area. Ideally, we'd like to have women participate in clinical trials. Otherwise, these patients continue on HER2-directed drugs with chemotherapy.

Editor’s Note: This interview took place prior to the FDA approval of adjuvant T-DM1 for HER2-positive early breast cancer.

References

1. Geyer Jr CE, Huang C-S, Mano MS, et al. Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: primary results from KATHERINE. Presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract GS1-10. abstracts2view.com/sabcs18/view.php?nu=SABCS18L_1226&terms=.
2. Murthy R, Borges VF, Conlin A, et al. Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19(7):880-888. doi: 10.1016/S1470-2045(18)30256-0.