The Phase II MutHER Study of Neratinib Alone and in Combination with Fulvestrant in HER2-Mutated, Non-amplified Metastatic Breast Cancer.

PURPOSE: HER2 mutations (HER2mut) induce endocrine resistance in estrogen receptor-positive (ER+) breast cancer. PATIENTS AND METHODS: In this single-arm multi-cohort phase II trial, we evaluated the efficacy of neratinib plus fulvestrant in patients with ER+/HER2mut, HER2 non-amplified metastatic breast cancer (MBC) in the fulvestrant-treated (n = 24) or fulvestrant-naïve cohort (n = 11). Patients with ER-negative (ER-)/HER2mut MBC received neratinib monotherapy in an exploratory ER- cohort (n = 5). RESULTS: The clinical benefit rate [CBR (95% confidence interval)] was 38% (18%-62%), 30% (7%-65%), and 25% (1%-81%) in the fulvestrant-treated, fulvestrant-naïve, and ER- cohorts, respectively. Adding trastuzumab at progression in 5 patients resulted in three partial responses and one stable disease ≥24 weeks. CBR appeared positively associated with lobular histology and negatively associated with HER2 L755 alterations. Acquired HER2mut were detected in 5 of 23 patients at progression. CONCLUSIONS: Neratinib and fulvestrant are active for ER+/HER2mut MBC. Our data support further evaluation of dual HER2 blockade for the treatment of HER2mut MBC.

Duke Scholars

Author Paul Kelly Marcom Medicine, Medical Oncology

Author Gretchen Genevieve Kimmick Medicine, Medical Oncology