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

Purpose: HER2 mutations (HER2(mut)) 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+/HER2(mut), HER2 non-amplified metastatic breast cancer (MBC) in the fulvestrant-treated (n = 24) or fulvestrant-naive cohort (n = 11). Patients with ER-negative (ER-)/HER2(mut) 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-naive, 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 HER2(mut) were detected in 5 of 23 patients at progression. Conclusions: Neratinib and fulvestrant are active for ER+/ HER2(mut) MBC. Our data support further evaluation of dual HER2 blockade for the treatment of HER2(mut) MBC.

Automated summary

This study evaluated the efficacy of neratinib plus fulvestrant in patients with ER+/ HER2(mut) MBC and found that the combination therapy had activity against the disease. It was also found that adding trastuzumab could control the disease effectively in patients with disease progression, and the clinical benefit rate was associated with histology and the type of HER2 mutation.