Adjuvant Neratinib Could Reduce Distant Breast Cancer Recurrence

ExteNET findings suggest a 1-year course of neratinib after trastuzumab-based therapy combats clinically relevant HER2-positive breast cancer relapse over 5 years

medwireNews: Use of neratinib after neoadjuvant and adjuvant chemotherapy plus trastuzumab reduces the risk of recurrent invasive disease in women with operable HER2-positive breast cancer, report the ExteNET investigators.

“[One] year of extended adjuvant therapy with neratinib […] significantly reduced 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”, the team writes in The Lancet Oncology.

After a median of 5.2 years, the 1420 patients who were randomly assigned to receive neratinib 240 mg/day for 1 year had a significantly lower rate of invasive disease events than their 1420 counterparts who were given placebo, at 116 versus 163 events.

This gave a 5-year invasive disease-free survival (DFS) rate of 90.2% for the neratinib-treated patients and 87.7% for controls, with a stratified hazard rate (HR) of 0.73 after adjusting for hormone receptor and nodal status, and whether chemotherapy and trastuzumab were given sequentially or concurrently.

Of note, the Kaplan–Meier curves for this endpoint separated at around 3 months and remained so for the remainder of follow-up, say Miguel Martin, from Universidad Complutense in Madrid, Spain, and co-authors.

Overall DFS including ductal carcinoma in situ and distant DFS were also significantly improved with neratinib use, as was time to distant recurrence, with HRs of 0.71, 0.78 and 0.79, respectively.

However, forest plot subgroup analysis showed that among the 1631 patients with hormone receptor-positive disease, the HR for invasive DFS was a significant 0.60 for the neratinib-treated participants versus controls. By contrast, the HR was not significant for the 1209 patients with hormone receptor-negative disease.

“The apparent efficacy of neratinib in HER2-positive, hormone receptor-positive tumours, which is not evident with other HER2-directed agents in the adjuvant setting, could be attributable to bidirectional crosstalk between oestrogen receptor and HER2 receptor signalling”, the authors hypothesize.

In addition, the HR for invasive DFS was 0.70 for the 2297 patients who initiated neratinib within a year of receiving trastuzumab versus the 543 patients who received neratinib more than a year after ending trastuzumab.

The researchers caution that the number of these events was small and describe the test of interactions as being “far from significant” but nevertheless note that this outcome is “consistent with the relapse pattern of HER2-positive tumours treated with adjuvant trastuzumab, since the relapse rate increases soon after the end of trastuzumab therapy.”

The primary safety analysis at 2 years, performed in 2816 patients who had received at least one study dose, showed that diarrhoea was the most common grade 3 adverse event associated with neratinib (40 vs 3% with placebo), followed by vomiting (3 vs <1%) and nausea (2 vs <1%). Serious treatment-emergent adverse events occurred in 7% of the neratinib arm and 6% of the placebo group, most commonly diarrhoea (22 vs one events), vomiting (12 vs one) and dehydration (nine vs one).

Dose reductions were required to manage treatment-emergent adverse events in 31% of the neratinib-treated patients and 2% of controls, with discontinuation required in 28% and 5%, respectively, the authors say, noting that loperamide prophylaxis for neratinib-associated diarrhoea is now under investigation.

However, there was no evidence to suggest that neratinib was associated with an increase in the long-term risk of symptomatic cardiac toxicity or second primary malignancies, or with serious late sequelae, such as chronic intestinal disease, report Miguel Martin et al.

Setting the ExteNET findings in context, Mariana Chavez-MacGregor and Elizabeth Mittendorf, from the University of Texas MD Anderson Cancer Center in Houston, USA, say that the excellent outcomes for node-negative patients given paclitaxel plus trastuzumab will make it hard to justify the addition of agents such as neratinib.

“For patients with node-positive breast cancer, we will probably add or extend therapies based on each patient's individual risk: those at high risk will receive greater benefit from additional treatment”, they write in a linked comment.

“Although the subgroup analyses in ExteNET are only exploratory, some doctors might feel more comfortable prescribing neratinib in patients with at least four positive lymph nodes or hormone receptor-positive tumours within 1 year of trastuzumab treatment”, Mariana Chavez-MacGregor and Elizabeth Mittendorf conclude.

“It will be a difficult balancing act—a shared decision-making process—in which we must balance the small benefit in outcomes with the not so minimal costs and side-effects.” 


Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol; Advance online publication 13 November 2017. DOI:

Chavez-MacGregor M, Mittendorf EA. Extended adjuvant therapy in patients with HER2-positive breast cancer: some answers, even more questions. Lancet Oncol; Advance online publication 13 November 2017. DOI:

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