Adjuvant Neratinib May Combat Post-Trastuzumab Invasive Breast Cancer

Women given neratinib after adjuvant chemotherapy and trastuzumab may have a reduced risk of invasive breast cancer

medwireNews: ExteNET trial findings indicate that 12 months of treatment with neratinib after completion of adjuvant chemotherapy and trastuzumab could reduce the likelihood of invasive disease in women with early-stage, HER2-positive breast cancer.

“[I]n patients considered to have a heightened risk of breast cancer relapse even after adjuvant chemotherapy and trastuzumab (eg, those with a heavy nodal burden, younger age, or locally advanced disease at diagnosis), neratinib could offer additional benefit”, suggest the investigators.

The 1420 women who were randomly assigned to receive the oral irreversible tyrosine kinase inhibitor of HER1, HER2 and HER4, at a dose of 240 mg/day for 12 months, experienced significantly fewer invasive disease events over 2 years of follow-up than the 1420 placebo-treated controls, at 70 versus 109 and a stratified hazard ratio (HR) of 0.67.

Invasive disease events were defined as invasive ipsilateral tumour recurrence, invasive contralateral disease, the development of local, regional or invasive recurrence, or death from any cause.

The primary endpoint of invasive disease-free survival was achieved by 93.9% of neratinib-treated patients compared with 91.6% of controls, report lead author Arlene Chan, from the Breast Cancer Research Centre–Western Australia, Perth, and co-workers.

Neratinib treatment was also associated with a significant increase in the rate of disease-free survival including ductal carcinoma in situ compared with placebo (93.9 vs 91.0%, HR=0.63), although secondary endpoints of distant-free survival and time to distant recurrence did not significantly differ between the treatment groups.

In addition, prespecified subgroup analysis detected a significantly greater invasive disease-free survival benefit for neratinib versus placebo in women with hormone receptor-positive breast cancer than their hormone receptor-negative counterparts with HRs of 0.51 versus 0.93.

This result is “of particular interest”, the authors write in The Lancet Oncology, as it is contrary to earlier studies of adjuvant and neoadjuvant anti-HER2 treatment indicating that hormone receptor status had no impact on outcome or that a negative status was of benefit.

Hypothesising that neratinib’s mechanism of action may preferentially increase HER2 pathway inhibition in hormone receptor-positive patients, the team comments: “With longer follow-up and elucidation of the mechanism of benefit in hormone receptor-positive patients, patient subgroups might be identified who could benefit the most from extended adjuvant therapy with neratinib.”

As previously reported, diarrhoea was the most common treatment-emergent event in neratinib-treated patients, with grade 2, 3 and 4 symptoms reported by 33%, 40% and less than 1% of patients, respectively. The corresponding rates in placebo-treated patients were 7%, 2% and 0%.

Diarrhoea was “mostly self-limiting” but led to dose reduction in 26% of patients, discontinuation in 17% and hospital admission in 1%. Grade 3 diarrhoea occurred after a median of 8 days and lasted for a median of 5 days; the researchers note that prophylactic loperamide in the first neratinib cycle is now being assessed in an open-label trial for this side effect. 


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; Advance online publication 10 February. DOI:

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