Background: Neratinib is indicated in Europe for the extended adjuvant treatment of patients with HER2-positive/HR-positive early breast cancer having completed trastuzumab-based therapy less than one year ago. Here we report post-hoc analyses of the HR-positive subgroup (N=1’631) from the ExteNET-trial (neratinib vs. placebo) performed for the German health technology assessment (HTA) procedure.

Methods: The study endpoints were re-analyzed according to local HTA requirements. For the evaluation of efficacy time-to-event endpoints, stratified Cox regression models were used. The evaluation of tolerability endpoints was performed in the same way based on non-stratified models and tests. Patient-reported endpoints were analyzed using a mixed model for repeated measures. Overall survival analyses have not been performed, as - in accordance with the study protocol - the required number of events (248 deaths) had not been reached at the time-point of HTA [Nov. 2019].

Results: Baseline characteristics in the analyzed population were well balanced between treatment arms, comparable with the overall ExteNET-population and consistent with the typical configuration of patients with early breast cancer. The median treatment duration at the time of the primary data cut was 11.5 months in the neratinib and 11.9 months in the placebo arm. After a median follow-up of 2 years and in-line with the overall ExteNET-results, time-to-event analyses revealed a significant advantage in disease-free survival (DFS) for neratinib vs. placebo (HR [95%-CI]: 0.45 [0.29; 0.69]; p=0.0002). The incidence based analysis confirmed this benefit (RR [95%-CI]: 0.44 [0.29; 0.68]; p=0.0002). These results were consistent with the analysis of distant disease-free survival (DDFS; HR [95%-CI): 0.52 [0.32; 0,84]; p=0.0082). The analysis after 5 years of follow-up based on the latest data cut confirmed the 2-year results, with 7.4% of patients in the neratinib and 13.0% of patients in the placebo arm having experienced at least one relapse event. The time-to-event analysis supported the significant advantage with regards to the DFS (HR [95%-CI]: 0.57 [0.41; 0.78]; p=0.0005), with a 5-year DFS-rate of 91.2 vs. 86.8%. These results were again consistent with the DDFS analysis (HR [95%-CI]: 0.60 [0.42; 0.85]; p=0.0037), with a 5-year DDFS-rate of 92.7 vs. 88.7%. The neratinib tolerability profile is consistent with class effects and thus predictable for the inhibition of HER-receptors, with domination of gastrointestinal (especially diarrhea; all grades: 94.4%; grade 3: 39.4%; cumulative duration all grades: 54.5 days; no systematic diarrhea prophylaxis), general (especially fatigue; all grades: 28.1%; grade 3: 1.9%) and cutaneous (especially rash; all grades: 14.3%; grade 3: 0.4%) events. No cumulative or irreversible toxicities have been observed. As shown in the CONTROL study and instituted via a risk management plan, adequate diarrhea prophylaxis and management can reduce the frequency (all grade: 79.6-96.7%), cumulative duration (all grades: 14.0-24.0 days) and severity of diarrhea (grade 3: 15.0-33.7%).

Conclusion: Extended adjuvant neratinib provides a clinically relevant benefit with further reduction of relapse risk in the curative situation of patients with HER2-positive/HR-positive early breast cancer. Accordingly, German HTA-authorities have granted an added benefit for this new treatment option.

Citation Format: Diana Lüftner, Hans Tesch, Marcus Schmidt, Andreas Hartkopf, Sarah Streicher, Anna Resch, Luca Genovese, Christian Rosé, Roberta Valenti, Nadia Harbeck. Neratinib as extended adjuvant therapy in patients with HER2-positive/HR-positive early breast cancer: HTA-driven analyses from the ExteNET study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-28.