Clin Cancer Res 2022 Jan 19
The Phase II MutHER Study of Neratinib Alone and in Combination with Fulvestrant in HER2-Mutated, Non-amplified Metastatic Breast Cancer.   
HER2 mutations (HER2) induce endocrine resistance in estrogen receptor-positive (ER) breast cancer.
In this single-arm multi-cohort phase II trial, we evaluated the efficacy of neratinib plus fulvestrant in patients with ER/HER2, HER2 non-amplified metastatic breast cancer (MBC) in the fulvestrant-treated ( = 24) or fulvestrant-naïve cohort ( = 11). Patients with ER-negative (ER)/HER2 MBC received neratinib monotherapy in an exploratory ER cohort ( = 5).
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 HER2 were detected in 5 of 23 patients at progression.
Neratinib and fulvestrant are active for ER/HER2 MBC. Our data support further evaluation of dual HER2 blockade for the treatment of HER2 MBC.

Related Questions

If NGS was positive would you treat with HER2 directed therapy? Is this a different clone and should be treated as such?