Martin M, et al. - Researchers here aimed to present the updated efficacy and long-term toxicity findings of neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET). They recognized a significant reduction in the proportion of clinically relevant breast cancer relapses (—ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast—without increasing the risk of long-term toxicity) with 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab at the 5-year follow-up. They planned an analysis of overall survival after 248 events.

Methods

• Researchers performed this ongoing randomised, double-blind, placebo-controlled, phase 3 trial.
• Eligible women were aged 18 years or older (≥20 years in Japan) with stage 1–3c (modified to stage 2–3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry.
• They randomly assigned (1:1) eligible patients via permuted blocks in accordance to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1–3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vsconcurrently with chemotherapy)
• The patients were then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo.
• They provided treatment continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred.
• Regarding treatment allocation, patients, investigators, and trial funder were masked.
• For this study, the predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat.

Results

• From July 9, 2009, to Oct 24, 2011, researchers identified 2,840 eligible women with early HER2-positive breast cancer from community-based and academic institutions in 40 countries.
• These patients were randomly assigned to receive neratinib (n=1420) or placebo (n=1420).
• Patients in the neratinib group indicated markedly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57–0·92, p=0·0083) after a median follow-up of 5·2 years (IQR 2·1–5·3).
• In the neratinib group, the 5-year invasive disease-free survival was 90·2% (95% CI 88·3–91·8) and in the placebo group was 87·7% (85·7–89·4).
• Compared with the placebo group, the most common grade 3–4 adverse events in the neratinib group were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]) without diarrhoea prophylaxis. 
• They observed treatment-emergent serious adverse events in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group.
• They identified no increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea with neratinib compared with placebo.