Endocrine resistance arising from HER2mutions (HER2mut) has been observed in estrogen receptor-positive (ER+) breast cancer. In this phase II single-arm multi-cohort study, researchers assessed the efficacy of neratinib plus fulvestrant in ER+/HER2mut, HER2 non-amplified MBC patients who had previously received fulvestrant (n=24) versus those who were treated with no therapy (n=11). In an exploratory ER-negative (ER−)/HER2mut MBC cohort, n=542 patients with ER-negative (ER−)/HER2mut MBC were treated with neratinib monotherapy (n=5). In the fulvestrant-treated, fulvestrant-naïve, and ER-cohorts, the CBR was 38% (18%–62%), 30% (7%–65%), and 25% (1%-81%), respectively. Hence, 3 partial improvements and one persistent disease of 24 weeks or longer were observed in 5 patients who received trastuzumab at progression. CBR was positively associated with lobular histology and negatively associated with HER2 L755 changes. Furthermore, 5 of 23 patients with advanced HER2-positive disease had acquired HER2mut at the time of clinical progression. ER+/HER2mut MBC treatment options include neratinib and fulvestrant. The data enable further study of dual HER2 blockade for the treatment of HER2mut MBC.
