EMA Initiates Official Regulatory Review of Neratinib in HER2+ Breast Cancer

Alan H. Auerbach

The European Medicines Agency (EMA) has validated the marketing authorization application 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 validation confirms the completion of the submission process and starts the formal review by the Committee for Medicinal Products for Human Use (CHMP) and the subsequent final approval decision by the European Commission.

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 (HR, 0.67; P = .009).

“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,” Alan H. Auerbach, CEO and president of Puma, said in a statement. “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.”

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.

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.

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 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).

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%.

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 Oncol. 2016;17(3):367-377.