Abstract PS3-11-21: A real-world prospective observational multi-national study in adult patients with breast cancer treated with extended adjuvant neratinib: interim results from the NERLYFE study

Abstract Background Neratinib, a pan-HER tyrosine kinase inhibitor, is approved in Europe as extended adjuvant therapy for HR+/HER2+ early breast cancer (EBC) in patients who have completed trastuzumab-based therapy ≤ 1 year ago. In this population, the ExteNET trial for patients with HR+/HER2+ EBC demonstrated a clinical benefit for neratinib vs. placebo, including significantly improved 5-year invasive disease-free survival (iDFS) (iDFS; Δ5.1%, HR 0.58, 95% CI 0.41-0.82). Neratinib-associated diarrhoea was the most common adverse event (39% Grade 3 without mandatory prophylaxis). Real-world data are essential for informing the management of diarrhoea and understanding patterns within its approved indications. Methods NERLYFE is a European, prospective, observational post-authorization safety study (PASS) conducted in routine clinical practice across Austria, Czech Republic, Germany, and the United Kingdom. Patients with HR+/HER2+ EBC were scheduled to receive neratinib as extended adjuvant therapy for up to 12 months in accordance with the EU SmPC. The primary objective is to describe the incidence of permanent treatment discontinuation due to diarrhoea during the first 3 months (mo) of neratinib treatment (core phase). Secondary objectives include describing the pattern of diarrhoea and maintenance of neratinib treatment. Results At data cut-off on 31 December 2024, 113 patients received at least one dose of neratinib and were observed for at least 3 months. Results of this pre-planned interim analysis are reported. Baseline characteristics were median age 55 years, 86% ECOG PS 0, 79% high risk of recurrence (AJCC stage I or N+ or non-pCR after neoadjuvant treatment). Overall, 56%, 28% and 11% of patients received adjuvant/post-neoadjuvant trastuzumab monotherapy, trastuzumab-emtansine (T-DM1), and trastuzumab/pertuzumab, respectively, with 5% of patients receiving other anti-HER2 therapy. The initial dose of neratinib was 240 mg/day for 61% of patients and 240 mg/day for 39%; 63% of patients received anti-diarrhoeal prophylaxis at least once. Fourteen percent of patients permanently discontinued neratinib due to diarrhoea within the first 3 mo of neratinib treatment, primarily within the first 2 mo of treatment. The diarrhoea-related neratinib discontinuation rate was lower in patients who received anti-diarrhoeal prophylaxis vs. those who did not (10% vs. 21%) and in those who started below vs. at 240 mg/day (12% vs. 15%). Any grade diarrhoea occurred in 88% of patients (20% Grade 3): 86% and 91% in the prophylaxis/non-prophylaxis groups respectively, and 82% vs. 91% in the below vs. at 240 mg/day group. No Grade 4 or 5 event was reported. Median time to first diarrhoea was within the first 7 days. Among patients receiving prophylaxis, the median cumulative duration of Grade ≥3 diarrhoea was 6.5 days versus 13 days without prophylaxis. Corrective treatment was used in 66% of patients. Treatment-emergent adverse events (TEAEs) other than diarrhoea were reported in 55% of patients, mostly Grade 1-2 gastrointestinal events. Three patients experienced serious TEAEs, including one diarrhoea event. Conclusion Anti-diarrhoeal prophylaxis was associated with a reduction in the incidence of diarrhoea occurrence (any grade), rate of neratinib discontinuation, and duration of Grade ≥3 diarrhoea. The overall safety profile of neratinib was consistent with the EU SmPC. These real-world findings support the benefit of anti-diarrhoeal prophylaxis and the use of neratinib in HR+/HER2+ early breast cancer patients in the current treatment landscape. Citation Format: D. Baerens, A. Waqas, G. Dagmar, A. Jegannathen, T. Sarkodie, P. Seropian, V. Bjelic-Radisic, M. Elnaggar, P. Staib, B. Lex, N. Harbeck, C. Jackisch, M. Schmidt, J. Suissa, A. Zkik, O. Dialla, R. Bartsch. A real-world prospective observational multi-national study in adult patients with breast cancer treated with extended adjuvant neratinib: interim results from the NERLYFE study abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-11-21.