Neratinib Improves DFS in HER2-Positive Breast Cancer

Treatment with the tyrosine kinase inhibitor neratinib demonstrated a 2-year disease-free survival rate of 93.9% in patients with early-stage HER2-positive breast cancer, representing a 33% improvement compared with placebo.

Alan H. Auerbach

Treatment with the tyrosine kinase inhibitor neratinib demonstrated a 2-year disease-free survival (DFS) rate of 93.9% in patients with early-stage HER2-positive breast cancer, representing a 33% improvement compared with placebo, according to findings from the phase III ExteNET study published in The Lancet Oncology.1

In the phase III study, which was also presented at the 2015 ASCO Annual Meeting, the 2-year DFS rate with placebo was 91.6% (HR, 0.67; 95% CI, 0.50-0.91; P = .009). In patients with both HER2- and HR-positive 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).

"ExteNET represents the first randomized trial to demonstrate a statistically significant DFS benefit using a HER2-targeted drug in the extended adjuvant treatment of patients with early-stage HER2 positive breast cancer who have previously been treated with adjuvant trastuzumab," Alan H. Auerbach, chief executive officer and president and chairman of the board of Puma, said in a statement. "We are pleased that The Lancet Oncology has chosen to publish these results."

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). Neratinib was administered for 12 months at 240 mg per day. Across both arms, trastuzumab and chemotherapy were administered concurrently in approximately 62% of patients, with 38% receiving the drugs sequentially. The interval between receiving trastuzumab and entering the trial was approximately 4.5 months.

The median age of patients in the study was 52 years. Approximately 23.8% of patients had node-negative disease, 46.6% had 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 HR-positive breast cancer.

The primary endpoint of the study was invasive DFS at 2 years. Secondary outcome measures focused on DFS in patients with DCIS, CNS recurrence incidence, and 5-year overall survival (OS).

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 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).

Overall, 95.4% of patients treated with neratinib experienced all-grade diarrhea (39.9% was grade 3/4). Other gastrointestinal-related side effects 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%.

Other adverse events of special interest included QT prolongation, which was less common in the neratinib arm (3.5% vs 6.6%). Left ventricular ejection fraction abnormalities of grade ≥2 were 1.3% with neratinib versus 1.1% with placebo.

In an early report from a phase II study exploring prophylactic loperamide,2 16% of patients experienced grade 3 diarrhea. The open-label study was initiated to address neratinib-associated diarrhea experienced by patients enrolled in the phase III ExteNET study, in which patients did not receive prophylactic loperamide.

“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,” Auerbach said during a web presentation of the data. “The grade 3 diarrhea seen in the trial generally occurred during in the first 28 days, and the majority was seen in the first week.”

Puma plans to continue to evaluate additional patients in the amended cohort of the phase II study. Results are anticipated for the full cohort of 72 patients in 2016. The company plans to submit a new drug application to the FDA and European Medicines agency, based on findings from the ExteNET study and the open-label loperamide prophylaxis trial, noted Auerbach.


  1. 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
  2. Auerbach AH. Phase II open-label study to characterize incidence and severity of diarrhea in patients with early-stage HER2-positive breast cancer treated with neratinib and intensive loperamide prophylaxis [webcast]. Puma Biotechnology Update Call; December 21, 2015.