EMA Approval Sought for Neratinib in HER2+ Breast Cancer

Alan H. Auerbach

A marketing authorization application has been submitted to the European Medicines Agency (EMA) for neratinib as a potential extended adjuvant therapy for patients with HER2-positive early stage breast cancer following 12 months of trastuzumab (Herceptin), according to an announcement from the developer of the TKI, Puma Biotechnology.

The application was based on findings from the phase III ExteNET study, which were published in the Lancet Oncology. In this study, extended treatment with neratinib demonstrated a 2-year disease-free survival (DFS) rate of 93.9% compared with 91.6% in the placebo arm, representing a 33% improvement versus placebo.

In the United States, Puma plans to submit a new drug application (NDA) to the FDA within the next few months. This action was anticipated earlier in the year; however, the FDA requested a new statistical analysis of the ExteNET trial that censored for patients who missed 2 or more scheduled disease assessments prior to recurrence or death. The NDA will also include data from a phase II study that explored prophylactic loperamide to prevent neratinib-associated diarrhea.

"Neratinib may be able to provide this type of improvement to further help the patients with this disease. We look forward to working with the CHMP/EMA during their review of this submission," said Alan H. Auerbach, chief executive officer and president of Puma. "This submission marks the first step in the broader global registration plan for neratinib and Puma is working with the US FDA on the US NDA, the next submission currently anticipated in mid-2016."

In the phase III 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.

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).

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).

With the new statistical model required by the FDA for the NDA, 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).

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, which will be included in the NDA, 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.

"Although the use of trastuzumab in the adjuvant setting has led to a reduction in disease recurrence in patients with early stage HER2-positive breast cancer, there remains an unmet clinical need for further improvement in outcome in order to attempt to further reduce this risk of recurrence following trastuzumab therapy," said Alan H. Auerbach, Chief Executive Officer and President of Puma.

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.

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.