Neratinib Alone and in Combination With Fulvestrant in HER2-Mutated, Non-Amplified Metastatic Breast Cancer

HER2 amplification or overexpression occurs in approximately 20% of patients with breast cancer and is an important predictive biomarker for identifying benefit from HER2-targeted therapy. Mechanisms of HER2 activation include not only overexpression of the HER2 protein/amplification of the HER2 gene but also somatic mutations in HER2, which lead to the activation of the HER2 gene. These mutations are relatively uncommon (observed in 2%–3% of primary breast cancers and approximately 5% of metastatic breast cancers [MBCs]) and are more often noted in ER+/HER2− invasive lobular carcinomas. HER2 mutations (HER2^mut) have been implicated as a mechanism of resistance to endocrine therapy and are sensitive to the irreversible pan-HER inhibitor neratinib. Due to the cross-talk between the ER and HER2 pathways, there is a rationale to combine neratinib with endocrine therapy. In this single-arm phase II trial, the combination of neratinib and fulvestrant was evaluated in patients with ER+/HER2^mut MBC who were fulvestrant-naïve as well as pretreated, and as monotherapy in an ER cohort. The authors found that efficacy was influenced by histology and the specific HER2 mutation location, and responses were accompanied by changes that could be detected with serial ctDNA monitoring. Finally, the combination showed efficacy in heavily pretreated patients, including those who had received prior CDK4/6 inhibitor and mTOR inhibitor therapy. These results support further development of this combination as it represents a precision medicine approach, which would further delay the use of chemotherapy for this small subset of patients.