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. Experimental Design: 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-naïve cohort (n=11). Patients with ER-negative/HER2^mut MBC received neratinib monotherapy in an exploratory ER- cohort (n=5). Results: The clinical benefit rate (CBR: 95% CI) was 38% (18-62%), 30% (7-65%), and 25% (1-81%) in the fulvestrant-treated, fulvestrant-naïve, and ER- cohort, respectively. Adding trastuzumab at progression in 5 patients resulted in 3 partial responses and 1 stable disease {greater than or equal to}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. Conclusion: Neratinib and fulvestrant is active for ER+/HER2^mut MBC. Our data supports further evaluation of dual HER2 blockade for the treatment of HER2^mut MBC.