Options Shift Paradigm of Locally Advanced HER2+ Breast Cancer

Theresa Shao, MD

In locally advanced HER2-positive breast cancer, the additions of agents such as neratinib (Nerlynx) and pertuzumab (Perjeta) in the adjuvant setting, as well as pertuzumab in the neoadjuvant setting, have led to an improvement in invasive disease- free survival (iDFS) for patients, explained Theresa Shao, MD.

Neratinib was approved by the FDA in July 2017 for the extended adjuvant treatment of patients with early-stage, HER2-positive breast cancer following postoperative trastuzumab (Herceptin). The decision was based on findings from the phase III ExteNET trial and the phase II CONTROL trial. In the primary ExteNET analysis, the iDFS rate at 2 years was 93.9% with neratinib compared with 91.6% with placebo (stratified HR, 0.67; 95% CI, 0.50-0.91; stratified log-rank P-value [2-sided] = .0091).¹

Additionally, in December 2017, the FDA approved pertuzumab in combination with trastuzumab and chemotherapy as an adjuvant treatment for patients with HER2-positive early breast cancer at high risk for recurrence, which was based on findings from the APHINITY trial. In this study, the addition of pertuzumab demonstrated a 94.1% 3-year iDFS rate versus 93.2% for those who received trastuzumab/ chemotherapy and placebo, which led to an 18% reduction in the risk of developing invasive disease or death (HR, 0.82; 95% CI, 0.67-1.00; P = .047).²

Pertuzumab was previously approved in the neoadjuvant setting in combination with trastuzumab and chemotherapy for patients at high risk for metastases or death with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer.

“There are so many new advances in HER2-positive breast cancer treatment that hopefully we can incorporate pertuzumab into the neoadjuvant or adjuvant setting for patients with high-risk disease,” said Shao. “The most benefit we’re seeing [with neratinib] is in patients with estrogen receptor (ER)—positive breast cancer— [specifically], in the extended adjuvant HER2-positive setting in patients with ER-positive disease with higher tumor burden, like mostly node-positive disease. Hopefully, these patients can consider receiving neratinib in the adjuvant setting.”

OncLive^®: Could you discuss the use of pertuzumab in the locally advanced setting of breast cancer?

What data exist with neratinib in the adjuvant space?

There have been toxicity concerns with neratinib. How have we incorporated this agent into practice?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Shao, an assistant professor of hematology-oncology at Mount Sinai Hospital, discussed the neoadjuvant and adjuvant findings with pertuzumab as well as the adjuvant use of neratinib in patients with locally advanced HER2-positive breast cancer.Shao: With pertuzumab, the data we have in the neoadjuvant setting are in 2 studies, NEOSPHERE and TRYPHAENA, that I talked about [at this meeting]. We showed that the addition of pertuzumab as neoadjuvant therapy with chemotherapy and trastuzumab improved pathological complete response. In the adjuvant setting, we have the APHINITY data, in which the addition of pertuzumab to chemotherapy plus trastuzumab improved iDFS at 3 years.This is a small molecule, irreversible tyrosine kinase inhibitor of HER1/HER3/HER4. The study that I spoke about is the ExteNET trial, which looked at neratinib in the extended adjuvant therapy setting. Patients had prior treatment with trastuzumab, and they started this drug after 1 year of completing trastuzumab. This study showed that the addition of neratinib for another year has improved iDFS as well, and it was mostly seen in patients with ER-positive and node-positive disease. Therefore, patients with higher-risk disease, and also ER-positive disease, have benefit.The main concern from the study was that 40% of patients on study had grade 3 diarrhea; quite a high number of patients discontinued the therapy early on, so there was a lot of concern from the physicians and patients who [were unsure how to apply] this is if there is so much diarrhea.

With this type of toxicity, what would you suggest as supportive care for patients?

In addition, we didn’t have the pertuzumab data yet [when neratinib was approved], and it’s unclear whether the addition of pertuzumab—in the neoadjuvant or adjuvant setting—has any impact on neratinib use. [It is also unclear] whether neratinib is helpful for patients [who previously received] pertuzumab as well. The ExteNET study did not have any patients who received pertuzumab, so that was the concern initially with the drug being used.Subsequent to the ExteNET study, investigators did another study called the CONTROL trial, in which there was an additional diarrhea prophylaxis. In the ExteNET study, there was no diarrhea prophylaxis; patients took Imodium as needed. In CONTROL, they looked at 3 prophylactic regimens to see whether the diarrhea would improve, and they also saw that the diarrhea mostly happened in the first 1 to 2 cycles.

The addition of a prophylactic regimen for diarrhea could be helpful. In the study, they looked at 3 regimens: Imodium alone, Imodium plus budesonide, and Imodium with colestipol. Results found that for patients on prophylaxis with Imodium and colestipol, at least for the first cycle, there was a significant decrease in diarrhea—especially grade 3/4. Therefore, instead of 40% of patients having grade 3 diarrhea on the study, it is down to 10%. There is also a significantly lower discontinuation rate.

How have these additions to the armamentarium changed the prognosis for locally advanced HER2- positive breast cancer?

As a result, this seems to be more applicable if the patient is willing to give neratinib a try. Within the first cycle, we want to initiate Imodium plus colestipol as an antidiarrheal prophylactic regimen. Once you get through the initial cycle, patients seem to tolerate the drug much better. Then, the rate of diarrhea subsides significantly.Because of all these newer drugs in HER2-positive breast cancer, the prognosis for a patient with [this type of] breast cancer has really changed significantly. As you can see in the APHINITY study or in the neratinib studies, the 3- and 5-year iDFS rates for patients with locally advanced breast cancer are as high as 90%, which is amazing. There are also studies suggesting that patients with HER2-positive breast cancer may be doing the best, or at least as well as patients with ER-positive, HER2-negative breast cancer. This is so different from 10 years ago, where a patient with HER2-positive breast cancer had a very poor prognosis and they did much worse compared with patients who had ER-positive, HER2-negative disease.

References

1. Chan A, Delaloge S, Holmes FA, et al; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(3):367-377. doi: 10.1016/S1470-2045(15)00551-3.
2. von Minckwitz G, Procter M, de Azambuja E, et al; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122-131. doi: 10.1056/NEJMoa1703643.