Adjuvant Neratinib or T-DM1 Decreases Distant Recurrence Risk in HER2+ Early-Stage Breast Cancer


The introduction of adjuvant approaches reduced the risk of disease recurrence in HER2-positive, early-stage breast cancer.

Treatment with neratinib (Nerlynx) or ado-trastuzumab emtansine (T-DM1; Kadcyla) in the adjuvant setting was found to reduce the risk of recurrence in an epidemiologic model of HER2-positive, early-stage breast cancer compared with other therapies, according to data presented during the 2021 San Antonio Breast Cancer Symposium.1

Of patients with early-stage breast cancer, 15% to 20% will be HER2-positive. HER2-positivity is associated with more aggressive disease and an increased risk of recurrences. Currently, the standard of care is 1 year of trastuzumab with chemotherapy. Up to 24% of patients experience recurrence, according to data from long-term follow-up studies. The median follow-up was 11 years.

The APHINITY (NCT01358877), KATHERINE (NCT01772472), and the ExteNET (NCT00878709) trials showed the benefits of adjuvant and extended adjuvant treatments for preventing recurrence. However, patient population heterogeneity and different study designs make cross comparison difficult.

Investigators developed an epidemiologic model to simulate distant recurrence for 1000 patients with newly diagnosed HER2-positive early-stage breast cancer in all 3 trials. ExteNET evaluated neratinib vs placebo in the extended adjuvant setting in patients treated with trastuzumab (Herceptin)-based therapy within 12 months between 2009 and 2012. The APHINITY trial looked at pertuzumab plus trastuzumab vs placebo plus trastuzumab plus standard adjuvant chemotherapy in patients without neoadjuvant therapy treated between 2011 and 2014. The KATHERINE study looked at a T-DM1 vs trastuzumab in patients with pathological complete response following neoadjuvant therapy treated between 2013 and 2016.

Disease-free survival cursed from the trials were used to estimate the risk of distant recurrence when available. For the 2 subgroup analyses where they were missing, invasive disease-free survival curves were used. Both observed and estimated curves were extrapolated to the standard 10-year follow-up period. Additionally, investigators assumed that prevention of recurrence did not continue beyond the follow-up period.

The model’s outputs were distant recurrence for the treatment and control arms for each study and the avoided distant recurrence in the treatment and control arms.

The analysis found that the higher-risk populations had a greater absolute benefit of treatment. Over the 10-year time horizon, distant recurrences avoided per 1000 women ranged from 11 to 65. The no pathological complete response (pCR) in the intent-to-treat (ITT) and the no pCR HR-positive populations of the KATHERINE study and the no pCR/HR-positive population of the ExteNET study had the greatest modeled absolute treatment benefit.

In the ExteNET study’s ITT population, of the 143 events in the control arm, 18 distant recurrences were avoided. In the APHINITY’s study ITT population, of the 103 events in the control arm, 20 distant recurrences were avoided. In the ExteNET’s study HR-positive arm, of the 148 events in the control arm at baseline, 27 distant recurrences were avoided. In the HR-positive population of the Aphinity study, of the 61 events in the control arm, 11 distant recurrences were avoided.

In the KATHERINE study’s no pCR/ITT population, of the 255 events in the control arm, 64 distant recurrences were avoided. In the no pCR/HR-positive population, of the 239 events in the control arm, 41 distant recurrences were avoided. Similarly, in ExteNET’s no pCR/HR-positive population, of the 265 events at baseline, 65 distant recurrences were avoided.

Overall, a range of reductions in distant recurrence from HER2-targeted agents was observed. The analysis is ongoing to quantify the uncertainty of the modeled estimates. However, being able to estimate absolute treatment benefit over a standardized timeframe can help to better understand benefits across heterogeneous breast cancer trials.


  1. Veenstra D, Hendrix N, Dolan C, et al. Estimating the long-term risk of recurrence in patients receiving HER2-targeted agents in HER2+ early-stage breast cancer. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract P2-11-19.

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