Members of the Food and Drug Administration’s Oncologic Drugs Advisory Committee voted 12-4 in support of approval of neratinib for single-agent extended adjuvant treatment of adults with early-stage HER2-positive breast cancer who received prior adjuvant trastuzumab-based therapy.

Members voting during the May 24 meeting expressed concern about the broadness of the indication proposed by the drug’s maker, Puma Biotechnology, but the majority said the risk-benefit profile of the drug is sufficient to support approval, particularly given the unmet need for such an agent. Those voting against approval argued that more data are needed to identify subpopulations of patients who would be most likely to benefit from treatment in order to narrow the indication.

“The drug clearly has efficacy in HER2-positive breast cancer. … It’s an unmet need in terms of patients who relapse after neoadjuvant or adjuvant chemotherapy,” said temporary voting member Stanley Lipkowitz, MD, of the National Cancer Institute in Bethesda, Md., in explaining his “yes” vote.

“There are some unknowns that concern me. … I don’t think I would treat as broadly as the indication describes,” he said, adding that it would be very difficult to decide which patients to treat, and it would be nice to have more data that provide predictive biomarkers to help determine who should be treated. “But at the end of the day I think it’s useful to have this as an option for treating patients.”

Lori M. Minasian, MD, also a temporary voting member from the National Institutes of Health, agreed.

“I think the option should be available,” she said, adding that the analysis was thorough. However, she, too, questioned the proposed indication.

“I remain concerned that the indication is far too broad, and … I think we need greater understanding of which subsets of patients would be most responsive to this therapy,” she said.

Heidi D. Klepin, MD, of Wake Forest University in Winston-Salem, N.C. said she voted “yes” for similar reasons, despite concerns about the lack of data to help narrow the indication.

“I particularly felt it was important to support this indication because I think this is an unmet need, and I think the primary outcome is an important and relevant outcome for our patients, even though what we’re seeing effect-wise may be modest,” she said.

Patricia A. Spears, a breast cancer survivor and patient representative from Raleigh, N.C., however, voted against approval.

“I think it is important to get drugs out to patients, and I think this will benefit a certain subset of patients. I’m just not sure we know which ones yet. What we do is tend to put a lot of patients at risk to benefit just a few. We do that a lot,” she said.

She expressed concern that the treatment would be “tacked on to the end of trastuzumab” in too many cases without concern for whether the patient is likely to benefit.

Another member who voted no, Courtney J. Preusse, who was a consumer representative on the committee, said she struggled with the decision but ultimately decided that the benefit this drug adds beyond what already exists is “just not compelling.”

Neratinib is a kinase inhibitor that irreversibly binds to epidermal growth factor receptors, HER2, and HER4, and results of the phase III ExteNET trial presented to the committee by representatives of the applicant showed a statistically significant invasive disease-free survival benefit with treatment.

The invasive disease-free survival at 2 years in 1,420 patients with early stage HER2-positive breast cancer after adjuvant treatment with trastuzumab who were randomized to receive neratinib was 94.2%, compared with 91.9% in 1,420 who received placebo (stratified hazard ratio 0.66). Follow-up data from patients who reconsented to participate showed similar outcomes from 2 to 5 years post-randomization.

An exploratory subgroup analysis suggested a possible difference in the magnitude of benefit based on hormone receptor status, with a 51% reduction in recurrence risk among HR-positive patients, compared with a 7% reduction in HR-negative patients (hazard ratios, 0.49 and 0.93, respectively).

Some concern was raised regarding multiple amendments to the protocol during the study, but committee members who spoke about this expressed satisfaction with the way these issues were handled in terms of sensitivity analysis.

As for safety, diarrhea was the most frequently reported adverse reaction, occurring in 95% of treated patients. Grade 3 diarrhea occurred in 40% of treated patients. Additional data were presented showing that antidiarrheal prophylaxis was effective. Several patients who spoke during the public hearing portion of the meeting–some of whom had travel expenses paid by the applicant, said they either had no problem with diarrhea or that it was manageable. Nearly all of those who spoke during the open public hearing, including patients and family members, shared emotional stories about their personal battles with breast cancer and urged the committee to support approval of neratinib to expand the options available to patients.

The FDA will now consider the new drug application for neratinib, and although it is not bound by the advisory committee’s recommendation, it usually follows such recommendations.

The advisory committee members reported having no relevant conflicts of interest.


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