Piling on Drugs to Treat HER2-Positive Breast Cancer

THE FIRST TARGETED TREATMENT for breast cancer that overexpresses the protein HER2 was approved in 1998, vastly changing the therapeutic landscape for women with this disease subtype.

That drug, Herceptin (trastuzumab), no longer stands alone. Since then, the FDA has approved four additional targeted therapies that can help improve outcomes for women with HER2 (human epidermal growth factor receptor 2)-positive breast cancer, which is aggressive and associated with lower overall survival. The most recent, Nerlynx (neratinib), was approved recently.

With several options available, efforts now focus around refining, combining and sequencing these treatments. Doctors and scientists are working to figure out how to predict which patients will benefit from presurgical or extended treatment with HER2- targeted therapies, and how to treat patients with triple-positive breast cancer, which is driven not only by HER2, but also by hormones.

Experts discussed those issues during a recent OncLive Peer Exchange® panel moderated by Adam M. Brufsky, M.D., Ph.D. OncLive® is part of the family of publications that includes CURE®.

WHO SHOULD GET HERCEPTIN?

Due to a broadening of the pathologic criteria that define the subtype, more patients than ever are being diagnosed with HER2-positive disease.

Unfortunately, this can lead to some patients being put into that category even though targeted therapies for the subtype won’t help them.

The panelists indicated that this variability among patients classified as having HER2-positive disease highlights the need for ways to improve patient categorization, making it more possible to predict response to anti- HER2-targeted therapies.

In the meantime, Herceptin should be considered for all patients classified as having early-stage HER2-positive disease in the presurgical setting, even if the PAM50 or 70-gene assays predict low therapeutic response or low genomic risk, some of the panelists agreed. One exception might be smaller tumors that have not spread to any lymph nodes — in those cases, surgery might come first.

Considering the low toxicity of Herceptin, “you need to have a very strong reason not to give it,” said Aditya Bardia, M.B.B.S., M.P.H, a medical oncologist at Massachusetts General Hospital. Kimberly Blackwell, M.D., professor of medicine at the Duke Cancer Institute, added that the importance of preventing recurrence is worth the risk of using Herceptin to treat an early-stage, low-risk tumor, even if it’s not entirely clear that the tumor will respond.

TREATING TRIPLE-POSITIVE DISEASE

Triple-positive breast cancer is not only HER2-positive, but is also driven by the hormones estrogen and progesterone. This can complicate treatment, because the hormonal activity interferes with the effectiveness of Herceptin and chemotherapy drugs, the experts pointed out.

For instance, in patients with metastatic, HER2-positive disease, estrogen receptor (ER) expression in more than 30 percent of cancer cells significantly predicted a lower probability of response to chemotherapy plus Herceptin, an analysis showed.

As a result, panelists said, treatment for these patients should involve combinations and sequences not only of chemotherapy and HER2-targeted drugs, but also of therapies that block the body’s production of cancer-fueling hormones. Known as endocrine therapies, these help to prevent the treatment resistance that can occur from targeting a single pathway.

The same principle is proving true, the panelists said, when two anti- HER2 therapies are used together, after chemotherapy has been completed, to maintain the benefit of previous treatments.

While these pairings tend to improve outcomes in patients with HER2-positive disease, those with locally advanced or metastatic triple- positive breast cancer may not benefit as much if inhibition of the HER2 pathway enhances ER signaling, Blackwell said. That’s why the PERTAIN study aimed to investigate whether adding endocrine therapy would improve response to dual HER2 blockade in postmenopausal patients with hormone receptor-positive and HER2-positive locally advanced metastatic breast cancer.

This open-label, phase 2 trial randomized participants one-to-one to receive Perjeta (pertuzumab), Herceptin and an aromatase inhibitor (AI), which stops the body from producing estrogen, versus only Herceptin and an AI. Some patients also received chemotherapy with docetaxel or paclitaxel 18 to 24 weeks before starting the AI/anti-HER2 therapy. A primary analysis showed that median progression-free survival was longer with the three-drug regimen than with the two-drug therapy (18.9 versus 15.8 months) and was generally well-tolerated.

According to Blackwell, these results support her practice of adding the AI therapy after chemotherapy in patients with triple-positive disease. Combining an AI with anti-HER2 agents after chemotherapy may be more effective than combining hormonal therapy with chemotherapy, as was done in a study known as B-52, Bardia said, and suggested the need for additional research on treatment sequences.

The panelists cautioned against directly comparing the B-52 and PERTAIN results, because the studies involved different patient populations (non-metastatic versus metastatic disease) and used different primary outcome measures (pathological complete response versus progression-free survival).

They agreed that optimizing the sequence of chemotherapy, endocrine treatment and HER2-targeted drugs for patients with triple-positive breast cancer will require further research to clarify the interactions between the ER and HER2 signaling pathways.

EXTENDED THERAPY WITH NERLYNX

In some later-stage disease, it can be beneficial to follow standard anti- HER2 treatment with another HER2 blocker, the panelists said. That drug, Nerlynx, is a tyrosine kinase inhibitor of HER1, HER2 and HER4, and also inhibits a different protein involved in some breast cancers, the epidermal growth factor receptor (EGFR). The drug’s most common side effect is diarrhea.

In the ExteNET trial, extended postsurgical therapy with Nerlynx demonstrated clinical activity in patients with HER2-positive metastatic breast cancer, even in those with prior exposure to other anti-HER2 agents and taxane-based chemotherapy. Findings showed that 12 months of Nerlynx significantly improved two-year disease-free survival (93.9 percent versus 91.6 percent with placebo) in patients with early-stage HER2- positive breast cancer who had completed Herceptin-based therapy before and after surgery less than two years prior to trial enrollment.

Extended therapy with Nerlynx was especially helpful in those with ER-positive disease. On this basis, the FDA approved Nerlynx on July 17, 2017. If additional studies support this use, it should be discussed with all patients who have triple-negative disease, even if they’ve been through standard treatment and are reluctant to take another drug, Blackwell said.

“Our job is to help (patients) participate in these decisions,” she said. “I’m going to have plenty of patients who say, ‘You’ve got to be crazy,’ but I will feel obliged to at least discuss it and document it in my notes.”

Extended therapy with Nerlynx is most appropriate for patients with large “HER2- addicted” tumors, metastasis to lymph nodes and disease that responds well to the initial regimen of HER2-targeted therapy, the panelists agreed.

Despite uncertainty about the clinical benefits, Blackwell said she tends to err on the side of overtreatment, provided that the patient can physically and financially tolerate the medication and the therapy does not definitively reduce duration of survival.

“For that individual patient sitting in front of me, I want to be able to say, ‘We’ve done everything within reason to prevent your breast cancer from coming back,’” she said.