The FDA approved the tyrosine kinase inhibitor neratinib for extended adjuvant treatment of early-stage HER2-positive breast cancer. The decision adds another treatment option to help prevent recurrence, but its relatively small potential benefit must be weighed against the risk of serious side effects.

The FDA has approved the tyrosine kinase inhibitor (TKI) neratinib (Nerlynx; Puma Biotechnology) for extended adjuvant treatment of early-stage HER2-positive breast cancer. The decision gives patients another treatment option to help prevent recurrence, although oncologists note that the drug's potential benefits may not outweigh its side effects in all patients.

The approval was based on results from the phase III ExteNET trial, which enrolled 2,840 women who were randomly assigned to receive either neratinib or placebo following adjuvant treatment with trastuzumab (Herceptin; Genentech). Investigators reported a small but statistically significant improvement in 2-year disease-free survival in women who took neratinib for 1 year versus placebo (94.2% vs. 91.9%).

About 40% of women taking neratinib experienced grade 3 or 4 diarrhea, which led to discontinuation of treatment in 17% of patients. As a result, the FDA recommended administering loperamide, an antidiarrheal prophylaxis, for the first 56 days of treatment.

Neratinib is thought to be a potentially more potent inhibitor of EGFR/HER2 signaling than lapatinib (Tykerb; GlaxoSmithKline)—a TKI that is approved for metastatic HER2-positive breast cancer—because it binds irreversibly to EGFR, HER2, and HER4. In contrast, lapatinib is a reversible inhibitor that targets only EGFR and HER2.

The challenge for oncologists is figuring out how best to incorporate this new therapy while limiting the risk of side effects, says Lori J. Goldstein, MD, chief of the Breast Service and professor of hematology-oncology at Fox Chase Cancer Center in Philadelphia, PA. In addition, it is unclear how neratinib will work in women who have been treated with pertuzumab (Perjeta; Genentech), an anti-HER2 monoclonal antibody approved for treatment of metastatic disease that is being considered for adjuvant treatment of early-stage disease.

In a phase III study, adding pertuzumab to adjuvant trastuzumab and chemotherapy led to statistically significantly higher disease-free survival compared with placebo in women with early-stage HER2-positive disease. If the combination is approved, it is likely that most women would take pertuzumab with trastuzumab in the first year of adjuvant treatment, says Roisin Connolly, MD, assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital in Baltimore, MD.

“More and more, we're realizing that we have to try to select the patients who really stand to benefit from all these extra agents, considering cost, potential side effects, and the risk of overtreatment,” says Connolly. “I would tend to consider neratinib only for higher-risk patients because the absolute benefit is small. Additional follow-up data beyond 2 years will also help determine the benefits for women over time.”

More research is needed to identify potential biomarkers of response to neratinib, says Goldstein. Although a subgroup analysis by the ExteNET investigators showed that women with hormone receptor (HR)–positive disease were more likely to benefit from neratinib than those with HR-negative tumors, the FDA did not include selection by HR status in the drug's indication.

“I will be very selective in recommending this to patients,” says Goldstein. “More investigation is needed into the interaction of HER family blockade and estrogen receptors.” –Janet Colwell