One year of treatment with neratinib after trastuzumab-based adjuvant therapy does not provide an overall survival (OS) benefit in patients with HER2-positive breast cancer, according to phase 3 results published in the European Journal of Cancer.

At 8 years, OS rates were similar between patients who received 1 year of neratinib and those who received placebo. However, the researchers noted that 8-year OS rates were high, at roughly 90% in both treatment groups.

This phase 3 study (ExteNET; Identifier: NCT00878709) included 2840 patients. They had stage I-IIIc (later amended to stage II-IIIc), HER2-positive breast cancer and had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab. 

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The patients were randomly assigned to receive neratinib at 240 mg daily (n=1420) or placebo (n=1420) for 1 year. Baseline characteristics were similar between the arms.

The median duration of study treatment was 11.6 months in the neratinib arm and 11.8 months in the placebo arm. The median follow-up was 8.0 years in the neratinib arm and 8.1 years in the placebo arm. Overall, 743 patients in the neratinib arm and 796 in the placebo arm completed 8 or more years of follow-up.

The 8-year OS rate was 90.1% in the neratinib arm and 90.2% in the placebo arm (stratified hazard ratio, 0.95; 95% CI, 0.75-1.21; P =.6914).

The researchers also assessed 8-year OS according to centrally confirmed HER2-positive status, hormone receptor (HR) status, and nodal status. Those results are outlined in the table below.

Patient Subgroup8-Year OS With Neratinib8-Year OS With PlaceboHazard Ratio
HR+ Disease (n=1631)91.6%90.1%0.80 (95% CI, 0.58-1.11)
HR- Disease (n=1209)88.1%90.3%1.18 (95% CI, 0.83-1.69)
Node-Negative (n=671)94.9%94.8%0.78 (95% CI, 0.40-1.48)
1-3 Positive Nodes (n=1328)91.8%90.6%0.81 (95% CI, 0.55-1.18)
4 or More Positive Nodes (n=841)83.8%85.9%1.17 (95% CI, 0.82-1.69)
Confirmed HER2+ (n=1796)91.2%90.8%0.86 (95% CI, 0.63-1.19)
Confirmed HER2+/HR+ (n=951)93.2%90.4%0.65 (95% CI, 0.41–1.03)
Confirmed HER2+/HR- (n=845)89.0%91.2%1.13 (95% CI, 0.73-1.76)

The anticancer treatments patients received after study treatment were largely similar between the neratinib and placebo arms. However, the researchers noted “a slight imbalance” in the use of trastuzumab — 5.2% in the neratinib arm and 6.9% in the placebo arm. 

In an exploratory analysis, the time to first subsequent anticancer treatment was longer in the neratinib arm than in the placebo arm (hazard ratio, 0.74; 95% CI, 0.58-0.94). Survival free from subsequent anticancer treatment was longer in the neratinib arm as well (hazard ratio, 0.79; 95% CI 0.64-0.98).

“This final analysis of the intention-to-treat population of the ExteNET trial did not demonstrate an overall survival benefit with extended adjuvant neratinib therapy versus placebo after a median follow-up of 8 years for women with early-stage HER2-positive breast cancer,” the researchers wrote. “The long-term survival of both the neratinib and placebo arms remained very high, with more than 90% of patients alive at 8 years.” 

Disclosures: This research was supported by Puma Biotechnology Inc. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Holmes FA, Moy B, Delaloge S, et al. Overall survival with neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): A randomised, double-blind, placebo-controlled, phase 3 trial. Eur J Cancer. Published online February 9, 2023. doi:10.1016/j.ejca.2023.02.002