NDA for Neratinib in HER2-Positive Breast Cancer Accepted by FDA

A new drug application (NDA) for neratinib as an extended adjuvant therapy for patients with HER2-positive breast cancer following prior treatment with postoperative trastuzumab (Herceptin) has been accepted by the FDA

Alan H. Auerbach

Alan H. Auerbach

A new drug application (NDA) for neratinib as an extended adjuvant therapy for patients with HER2-positive breast cancer following prior treatment with postoperative trastuzumab (Herceptin) has been accepted by the FDA, according to a statement from the developer of the TKI, Puma Biotechnology.

The application included findings from the phase III ExteNET study, in which neratinib demonstrated a 2-year disease-free survival (DFS) rate of 93.9% compared with 91.6% in the placebo arm, according to findings published inLancet Oncology. The FDA completes a standard review within 12 months from the time of submission, which was completed for neratinib on July 21, 2016.

“The FDA acceptance of our NDA is an important regulatory milestone,” Alan H. Auerbach, chief executive officer and president of Puma, said in a statement. “We look forward to working with the FDA during their review of this submission.”

The application was originally anticipated in the first quarter of 2016; however, the submission was delayed following a series of meetings with the FDA in which the agency requested a new statistical analysis of data from the ExteNET trial. For the new analysis, data were censored for patients who missed 2 or more scheduled disease assessments prior to recurrence or death.

With the new statistical model, the 2-year invasive DFS rates were 94.2% and 91.9% for neratinib and placebo, respectively. This represented a 34% reduction in the risk of disease recurrence or death (HR, 0.66; CI, 0.49-0.90;P= .004), according to data released by the company.

The NDA was based on the new statistical analysis of the ExteNET data, which has not yet been published. Additionally, further data were submitted from a phase II study exploring diarrhea prophylaxis with loperamide.

“The FDA requested that Puma include the results of this phase II trial that incorporated the loperamide prophylaxis with the NDA filing and stated that the potential to include this data in the label for neratinib would be a review issue and part of the labeling negotiation,” said Auerbach, when the delay was announced in March 2016.

In the ExteNET study, 2840 patients who remained disease-free following 1 year of treatment with adjuvant trastuzumab and chemotherapy were randomized to neratinib (n = 1420) or placebo (n = 1420). The interval between receiving trastuzumab and entering the trial was approximately 4.5 months. Neratinib was administered for 12 months at 240 mg per day.

The median age of patients in the study was 52 years and approximately 23.8% had node negative disease, with 46.6% of patients having 1 to 3 positive nodes and 29.6% had ≥4 positive nodes. Anthracyclines were administered as adjuvant chemotherapy in the majority of patients (77%). Appropriate endocrine therapy was administered to 94% of patients with hormone receptor (HR)-positive breast cancer.

In the data published inLancet Oncology, treatment with neratinib benefited patients across all subgroups for invasive DFS. Trends toward a greater benefit were seen in patients who were <35 years old at randomization (n = 101; HR, 0.43; 95% CI, 0.14-1.17) and those who received sequential trastuzumab and chemotherapy (n = 1070; HR, 0.48; 95% CI, 0.28-0.81). In patients with both HER2+ and HR+ disease, the 2-year DFS rate was 95.4% with neratinib and 91.2% with placebo, representing a 49% benefit (HR, 0.51;P= .001).

In the neratinib arm, 3.7% of patients experienced distant recurrence compared with 5.1% in the placebo arm. Central nervous system (CNS) metastases were seen in 0.9% of patients in the neratinib arm versus 1.1% with placebo.

In patients with DCIS, the 2-year DFS rate was 93.9% with neratinib versus 91.0% (HR, 0.63; 95% CI, 0.46-0.84;P= .002). In the HR-negative group (n = 1209) the 2-year invasive DFS rate was 92% with neratinib and 92.2% with placebo (HR, 0.93;P= .735).

Across the full study, 95.4% of patients treated with neratinib experienced all-grade diarrhea (39.9% was grade 3/4). The trial design did not mandate antidiarrhea prophylaxis. Other gastrointestinal-related adverse events (AEs) included nausea (43%), fatigue (27%), vomiting (26.2%), and abdominal pain (24.1%). In the placebo arm, 35.4% of patients had all-grade diarrhea, with a grade 3/4 incidence of just 1.6%.

A phase II study was launched to quantify the benefits of prophylactic loperamide for reducing neratinib-related diarrhea. Data from this study were presented during a webcast by Puma, and showed that grade 3 neratinib-related diarrhea was reduced to 16% with loperamide.

In the phase II open-label study, patients were enrolled within 1 year of completing adjuvant treatment with trastuzumab. Neratinib was administered at 240 mg daily for 12 months. In the original protocol, 27 patients received loperamide at 16 mg on day 1 followed by 12 mg per day on days 2 and 3 and 6 to 8 mg on days 4 to 56. After an amendment to the protocol to simplify treatment, 23 patients received loperamide at 12 mg per day for the first two weeks followed by 8 mg per day until day 56.

In the original protocol group, 18.5% of patients experienced grade 3 diarrhea (95% CI, 6.3-38.1). Of those who experienced a grade 3 event (n = 5), 60% were non-compliant to the loperamide regimen. In the amended group, the grade 3 diarrhea rate was 13% (95% CI, 2.8-33.6), and 67% of patients were non-compliant.

The rates of all-grade diarrhea were 74.1% and 43.5% in the original and amended protocol groups, respectively. Grade 4 diarrhea did not occur and hospitalizations were not required. Most treatment-emergent diarrhea occurred within the first 4 weeks.

&ldquo;The results of the study demonstrate that using the loperamide prophylaxis regimen reduced both the all-grade diarrhea and the grade 3 diarrhea down to much more acceptable levels than what was seen in the phase III ExteNET trial,&rdquo; said Auerbach, when findings from the phase II study were announced during a webcast in 2015.


Chan A, Delaloge S, Holmes FA, et al. 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 Oncology. doi:10.1016/S1470-2045(15)00551-3.

In high-risk patients, the 2-year DFS rate was 92.9% with neratinib and 89.8% with placebo (HR, 0.66;P= .01). In patients with centrally confirmed HER2-positive disease, the benefit with neratinib was 94.7% versus 90.6% with placebo (HR, 0.51;P= .002).

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