EMA DOES NOT APPROVE NERATINIB

In Europe, the breast cancer drug neratinib (Nerlynx, Puma Technology) has been given a negative opinion, which means that approval is not recommended.

The European Committee for Medicinal Products for Human Use (CHMP) was not impressed by the clinical data submitted from the pivotal trial of the drug, which showed only a small difference in efficacy between the drug and placebo, yet many patients experienced side effects with the drug. The CHMP therefore concluded that the benefits were not enough to outweigh the risk for side effects, and recommended that neratinib be refused market approval.

This must have come as a nasty surprise to the company involved, for it had submitted the same clinical data in the United States, and there, the US Food and Drug Administration approved neratinib in July 2017.

Neratinib is a tyrosine kinase inhibitor that targets HER2. It is intended for use in women with HER2+ breast cancer who have already been treated with the HER2 antibody trastuzumab (Herceptin, Roche/Genentech).

The clinical data that were submitted for the drug's approval come from the pivotal ExteNET phase 3 trial, which was conducted in 2840 women with early breast cancer with high levels of HER2. These women had already received treatment that included trastuzumab. They were randomly assigned to a year of daily treatment with either neratinib or placebo.

The CHMP notes that the main measure of effectiveness was the proportion of women who had lived without having their cancer return by the end of the 2-year study (the endpoint was invasive disease free–survival [iDFS]). This target was met in 94% of patients who received neratinib and in 92% of patients who received placebo.

"It is uncertain that this difference in benefit would be seen in clinical practice," the CHMP stated.

In addition, the CHMP pointed out that "neratinib causes side effects in the digestive system, particularly diarrhoea, which affected most patients and might be difficult to manage."

In the trial, almost 40% of patients experienced grade 3 diarrhea within the first 30 days of treatment, according to data presented at the 2015 San Antonio Breast Cancer Symposium.

In its approval of the drug, the FDA said that patients should be given the antidiarrheal drug loperamide (Imodium, Johnson & Johnson) for the first 56 days of treatment with neratinib and as needed thereafter.

Uncertainty Over Neratinib Benefit

When the results from the ExteNET study were published in November 2017 in the Lancet Oncology, an accompanying editorial and an outside expert both questioned how neratinib should be incorporated into breast cancer therapy, as previously reported by Medscape Medical News.

Patients in the ExteNET trial took trastuzumab for 1 year and then neratinib for another year, so they had a total of 2 years on HER2-targeted therapy, pointed out Lisa A. Carey, MD, professor of breast cancer research at the North Carolina Cancer Hospital, Chapel Hill. "It's not trivial. Patients are going through a lot for a little [benefit]."

A separate consideration is that neratinib is an oral drug, so with copays, considerable financial toxicity may be passed on to the patient, she added. (The wholesale cost of neratinib is estimated to be $126,000 for 1 year of therapy.)

"Even though it is a positive study, neratinib's role may be fairly limited," she told Medscape Medical News at the time. "We need a better clarity on who needs this drug and who will benefit from it," she emphasized.

Alexandra Zimmer, MD, from the Women's Malignancies Branch, Center for Cancer Research, the National Cancer Institute (NCI), raised similar concerns. In an NCI blog, she explained that despite the approval, because of several factors — the modest reduction in the recurrence rate, the fact that data on overall survival are not yet available, and the high rate of side effects — it is unlikely that neratinib will be widely used.

The FDA's approval of neratinib was met with criticism from the breast cancer advocacy group Breast Cancer Action. The executive director of the group, Karuna Jaggar, noted the high cost of treatment, minimal clinical benefit from a surrogate endpoint (iDFS), and the absence of survival data. "A so-called 'surrogate endpoint' like invasive disease–free survival that is not clinically significant may be useful in guiding the development of experimental treatments, but it cannot replace the outcome that patients and doctors ultimately care about: women actually living longer, or at least living better with fewer side effects," she noted.

"With the approval of neratinib, the FDA has once again approved an experimental drug that has not been shown to lengthen or improve breast cancer patients' lives — either by helping them live longer or live better, with fewer side effects," she wrote. "It means that thousands of cancer patients each year are exposed to expensive, toxic treatments that don't actually help them live longer," she said.