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ESMO 2017: Invasive DFS Rates Following Trastuzumab are Improved with Neratinib Over Placebo in Early Stage HER2-positive Breast Cancer

ExteNET at 5 years demonstrates significant clinical benefit following one-year of neratinib administered after one year of trastuzumab-based adjuvant therapy
08 Sep 2017
Cytotoxic Therapy
Breast Cancer

Invasive disease-free survival (iDFS) rates were significantly better in patients with early stage HER2-positive breast cancer treated with extended adjuvant neratinib, although at expense of a transient deterioration of health-related quality of life (HRQoL), according to findings from companion studies of a phase III ExteNET trial data presented during the ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.

Lead author Miguel Martin, head of Medical Oncology at the Hospital General Universitario Gregorio Marañón in Madrid, Spain presented efficacy findings from a pre-planned 5-year analysis of data from ExteNET, which evaluated the anticancer activity of neratinib after trastuzumab-based adjuvant therapy in patients with early stage HER2-positive breast cancer.

ExteNET has demonstrated a significant iDFS benefit at 2 years follow-up (primary endpoint) from the addition of a one year course of sequential neratinib over placebo in high-risk, HER2-positive, adjuvant trastuzumab pretreated, early breast cancer patients hazard ratio (HR) 0.67; 95% confidence interval (CI) 0.50, 0.91 (p = 0.0091).1

A pre-planned 5-year analysis to test whether neratinib could improve long-term survival was presented. In the phase III international, multicentre, double-blind, placebo-controlled ExteNET trial, patients were randomised to oral neratinib at 240 mg daily or to placebo for one year following their initial trastuzumab treatment. At 2 years post randomisation, consenting patients allowed data collection concerning disease recurrences and survival from medical records for a further 3 years. The analysis was on the intention-to-treat (ITT) population and non-consenting patients were censored at their last physical examination.

5-year invasive disease-free survival rates were significantly improved with neratinib compared to placebo

The updated 5-year efficacy findings from the analysis reported at the ESMO 2017 was done on 2840 patients in the ITT population comprising 1420 patients receiving neratinib and 1420 receiving placebo. Of these, 53 patients had died during the initial 2-year follow-up and 2117 (76%) patients consented to additional follow-up. HER2 was centrally confirmed in 1796 patients overall, including 90.4% of neratinib and 88.2% of placebo patients. Overall, 1209 patients were hormone receptor negative including 88.8% and 88.9% of patients in the neratinib and placebo arms, respectively (p = 0.762).

After a median follow-up of 5.2 years, 2810 patients in the ITT population demonstrated iDFS rates of 90.2% with neratinib versus 87.7% with placebo, HR 0.73; 95% CI 0.57, 0.92 (p = 0.008).


Caption line for figure: ExteNET: iDFS by hormone receptor status.

© Miguel Martin. 

Overall survival data are not yet mature.

Small changes in health-related quality of life were demonstrated

In a poster presentation at the ESMO 2017 Congress, Suzette Delaloge, Associate Professor of Medical Oncology Institut Gustave Roussy, Villejuif, France will present on 11 September shared findings from the longitudinal evaluation of HRQoL that was an exploratory endpoint of ExteNET trial. The breast cancer specific FACT-B and the general HRQoL EQ-5D questionnaires were completed at baseline and months 1, 3, 6, 9, and 12 by 2407 and 2427 patients, respectively.

Questionnaires’ compliance in this trial was more than 85%. The FACT-B was completed by 1171 patients on neratinib and by 1236 placebo patients and the EQ 5D was completed by 1186 and 1241 neratinib and placebo patients, respectively.

Changes in scores from baseline using ANCOVA (with no imputation for missing values) and sensitivity analyses using alternative methods were performed; changes in HRQoL scores were considered to be clinically meaningful if they were greater than the minimal clinically important differences (MCIDs) reported in the literature.

Neratinib was associated with a decrease in HRQoL scores at month one compared with placebo (adjusted mean differences: FACT-B total, –2.9 points; EQ-5D index, ‒0.02), after which the between-group differences diminished at later time-points. Except for the FACT-B physical well‑being (PWB) subscale at month one (–2.4), all between-group differences were less than MCIDs. Sensitivity analyses exploring missing data did not change these results.

The authors suggested neratinib-related diarrhoea was possibly associated with decreased HRQoL in PWB at month one.

Small improvements in the BCS scores favouring neratinib were reported; the mean difference in BCS scores was 0.3, 0.7, 0.4, 0.6, and 0.2 over the 5 time-points, all less than MCIDs.


Caption line for figure: ExteNET: Longitudinal HRQoL Changes from Baseline.

© Suzette Delaloge. 


One year of neratinib treatment after trastuzumab-based adjuvant therapy showed a long-term sustained effect that associated with a significantly improved iDFS at 5 years in patients with early stage HER2-positive breast cancer.  

Professor Martin and co-authors concluded that data from the protocol-specified subgroup analysis suggest that hormone receptor positive patients had a greater benefit from neratinib and that the secondary efficacy endpoints were supportive of the primary analysis.

Professor Delaloge and colleagues summarised that neratinib was associated with transient initial decreased HRQoL, particularly regarding physical well being, that may have been due to neratinib-related diarrhoea. The investigators concluded that the relatively small magnitude of differences observed over the time-points following month one in physical well being that favoured placebo and changes in the breast cancer scale BCS favouring neratinib may not be clinically important.

Hope S. Rugo, Professor of Medicine, Director, Breast Oncology and Clinical trials Education at University of California San Francisco Comprehensive Cancer Center who discussed the results of ExteNET trial said that the study showed continued demonstration of clinically significant benefit, particularly in higher risk, HR-positive disease despite limitations due to change in sponsor and initial plan for short follow-up. However, diarrhoea is a limiting factor, but it can be reduced significantly with prophylaxis, which is mandatory component of treatment. Survival data are pending and reduction in distant events is encouraging.


This trial was sponsored by Puma Biotechnology.


  1. Chan 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;17(3):367-377.


149O - Martin Jimenez M, et al. Neratinib after trastuzumab (T)-based adjuvant therapy in early-stage HER2+ breast cancer (BC): 5 year analysis of the phase III ExteNET trial.

177P – Delaloge S, et al. Effects of neratinib (N) on health-related quality of life (HRQoL) in early-stage HER2+ breast cancer (BC): longitudinal analyses from the phase III ExteNET trial.

Last update: 08 Sep 2017

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