Neratinib plus fulvestrant plus trastzuzumab is a promising combination for hormone receptor-positive (HR+), HER2-negative, HER2-mutant metastatic breast cancer (mBC): results from the phase II SUMMIT trial
Abstract: There is a promising combination of neratinib plus fulvestrant plus trastzuzumab (N+F+T) to patients with HR+/HER2-/HER2mut metastatic breast cancer, who pretreated with CDK4/6 inhibitor.
In breast cancer, HER2 mutations vary in frequency from 2% to 8%, depending on disease stage and histology and are associated with poor prognosis. Neratinib is a second-generation, pan-HER TKI that irreversibly binds to the ATP pocket of the tyrosine kinase domain of epidermal growth factor receptor (EGFR), HER2, and HER4. SUMMIT trail enrolled 45 patients with HR+, HER2-negative MBC with activating HER2 mutations who had previously been treated with a CDK4/6 inhibitor. The result of SUMMIT showed that objective response rate (ORR) and clinical benefit rate (CBR) of the N+F+T regimen reached 38% and 47%, respectively. Duration of response (DoR) was 14.4 months. In addition, it’s worth mention that the ORR of several HER2 allelic variants was 50% in V777L, 40% in L755S/P, 50% in S310F, 36% in exon 20 insertion. According to SUMMIT trail and another neratinib-related trial – MutHER, the National Comprehensive Cancer Network (NCCN) advises to consider neratinib ± fulvestrant / trastzuzumab and neratinib ± fulvestrant in certain circumstances for patients with HR+ or HR-/HER2- metastatic breast cancer with HER2 activating mutations who had received CDK4/6 inhibitor. (This recommendation was also added in NCCN Clinical Practice Guidelines in breast cancer version 1.2023, and the recommended evidence level is category 2B.)
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