Expert Highlights Nuances in HER2-Positive Breast Cancer Care

Zahi Mitri, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Zahi Mitri, MD

The adjuvant setting in HER2-positive breast cancer has become more varied over the past year, most recently with findings of the phase III PERSEPHEONE trial, which showed that 6 months of trastuzumab (Herceptin) was noninferior to the standard 12 months of the HER2-directed agent, supporting a shortened duration of treatment.¹

Additional data have shown activity with a combination in this setting, as well. Results from the phase III APHINITY trial showed that patients randomized to adjuvant pertuzumab (Perjeta), trastuzumab, and chemotherapy had a 3-year invasive-disease free survival (iDFS) rate of 94.1%, compared with 93.2% for patients receiving received trastuzumab plus chemotherapy and placebo (HR, 0.82; 95% CI, 0.67-1.00, P = .047).² At 4 years, the iDFS rates were 92.3% and 90.6%, respectively. In December 2017, the FDA approved the pertuzumab/trastuzumab plus chemotherapy regimen in this setting for those with early HER2-positive breast cancer at high risk for recurrence.

Neratinib (Nerlynx) is another agent that has shown promise in the adjuvant setting. In the phase III ExteNET trial, patients were randomized to placebo (n = 1420) or 240 mg of neratinib daily (n = 1420) for 1 year. At a median follow-up of 5 years, the iDFS rate was 90.2% and 87.7% in patients randomized to neratinib and placebo, respectively (HR, 0.73; 95% CI, 0.57-0.92; P = .0083).³ This agent was approved by the FDA in July 2017 for the extended adjuvant treatment of patients with early-stage, HER2-overexpressed/amplified breast cancer following 1 year of adjuvant trastuzumab.

OncLive: What are some of the key takeaways from your discussion of the evolving treatment landscape in HER2-positive breast cancer?

In an interview at the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Zahi Mitri, MD, assistant professor of medicine, Oregon Health and Science University, and chair of the meeting, discussed these adjuvant advances and other emerging trends in the treatment of patients with HER2-positive breast cancer.Mitri: The presentation at the 2017 San Antonio Breast Cancer Symposium on the NSABP B-47 trial showed and confirmed that patients who have HER2 amplification are those who benefit from HER2-directed therapy.

It is important to take away that the duration of adjuvant therapy is still 1 year of trastuzumab. At this point, there are a few studies that are looking at shorter duration of therapy. I touched on the APHINITY and the ExteNET trials. APHINITY added pertuzumab to adjuvant therapy with trastuzumab. ExteNET added 1 year of neratinib after completing 1 year of trastuzumab therapy.

What are your thoughts on the available adjuvant therapies?

In metastatic disease, I touched on the roles of pertuzumab, as well as ado-trastuzumab emtansine (T-DM1; Kadcyla), in the management of metastatic HER2-positive breast cancer and went over some of the new agents in development. These are exciting novel anti-HER2 therapies that are coming through the pipeline. The findings from the APHINITY study were statistically significant. However, at this point, we haven't changed much of our treatment. We still use pertuzumab for the indication it was approved—in the neoadjuvant setting for tumors greater than 2 cm or that are node positive.

A big question is, “What to do after these 6 cycles of neoadjuvant therapy? Do you give doxorubicin followed by 4 cycles of dual anti-HER2 therapy?” It's a big unknown. At this point, I’m giving patients 1 year of pertuzumab based on the FDA approval indication and the APHINITY trial. [Sometimes it’s given] as a neoadjuvant treatment and the rest of the time it is given in the adjuvant setting.

As for neratinib, the study was positive and continued to be positive at the 5-year follow up. This was after the first report at 3 years. That study remained positive with a 2% to 3% benefit. Most of the benefit seems to be in the estrogen receptor (ER)—positive subgroup, at around 45%.

Is giving neoadjuvant trastuzumab, pertuzumab, and chemotherapy, followed by surgery and adjuvant pertuzumab and trastuzumab common?

Is there a certain patient population you would consider giving neratinib to versus pertuzumab/trastuzumab with chemotherapy?

[It is important to note that] none of these patients received pertuzumab. Therefore, [we don’t know] what the potential benefit of neratinib is following 1 year of therapy with pertuzumab. I don't know if we'll ever get the answer to that based on the size of APHINITY and ExteNET. If I committed a high-risk patient with ER-positive disease to 1 year of therapy with pertuzumab, I recommend neratinib in the adjuvant setting. A lot of what we do at our institution is neoadjuvant therapy. We still give chemotherapy with an anti-HER2 blockade in the neoadjuvant setting. Following surgery, we used to complete just 1 year of therapy with trastuzumab. At that point, we are adding pertuzumab in patients who qualify for it. After 1 year is when we discuss neratinib with patients. In light of a recent subgroup analysis, there is a lot of talk on whether we should use pertuzumab for ER-negative/HER2-amplified breast cancer and neratinib for ER-positive/HER2-amplified breast cancer. At this point, the primary endpoint in both studies was positive. If you want to be a purist from a statistical standpoint, you have to give it to everyone. If you want to do subgroup analyses, it seems that most of the benefit with neratinib is in the ER-positive subgroup.

For pertuzumab, the benefit is similar in both, but more so in the ER-negative subgroup. At this point, I’m sticking to the primary endpoint of the study. If you think that someone deserves pertuzumab upfront, I'm at least offering neratinib on the back end. That being said, if someone has bad tolerance to one or the other, then we have to manage that. Though the overall survival was the same in the APHINITY study of pertuzumab and the ExteNET study of neratinib, the ER-negative subgroup did not seem to benefit.

References

1. Earl HM, Hiller L, Vallier A-L, et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. J Clin Oncol. 2017;36 (suppl; abstr 506).
2. von Minckwitz G, Procter MJ, De Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377:122-131. doi: 10.1056/NEJMoa1703643.
3. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017; 18(12):1688-700. doi: 10.1016/S1470-2045(17)30717-9.