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The SUMMIT study shows that the combination of neratinib, fulvestrant and trastuzumab is effective in HER2-mutant metastatic breast cancer after progression on CDK4/6 inhibitors
New data recently published on Annals of Oncology shows a clinically meaningful benefit for a combination of neratinib, fulvestrant and trastuzumab in HER2-mutant metastatic breast cancer, supporting the requirement of neratinib for efficacy of the triplet.
Results come from the phase II SUMMIT basket study evaluating neratinib-based therapy in patients with solid tumors harboring HER2 mutations. Neratinib, an oral, irreversible, pan-HER tyrosine kinase inhibitor with preclinical and clinical activity in patients with HER2-mutant tumors, has been shown to overcome endocrine resistance in hormone receptor-positive, HER2-mutant breast cancer cell lines and xenografts. In this study, patients with HER2-mutant metastatic breast cancer and prior CDK4/6 inhibitor therapy received neratinib+fulvestrant+trastuzumab (N+F+T), fulvestrant+trastuzumab (F+T) or fulvestrant alone; those whose disease progressed on F+T or fulvestrant could crossover to the triplet. The objective response rate of N+F+T treated patients was 39% (including one complete response and 21 partial responses)and median progression-free survival was 8.3 months; no responses occurred in fulvestrant- or F+T-treated patients; responses in patients crossing over to N+F+T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal (objective response rate of 39%) and lobular (objective response rate of 41%) histology, one or more HER2 mutations, and co-occurring HER3 mutations. As authors say, «In line with this result, neratinib-based combinations have recently been endorsed for a molecularly defined population of patients harboring HER2 activating mutations by National Comprehensive Cancer Network guidelines. Furthermore, 16 patients enrolled in this trial exhibited a HER2 mutation in DNA retrieved from archival biopsy, confirming these pathogenic alterations are present much earlier in tumor evolution. This implies that with future increased early utilization of NGS, and thus increased detection of HER2 mutations at the time of breast cancer diagnosis or at endocrine resistance, the results presented herein support future testing of neratinib-based combinations in patients with HR+ HER2-mutant early breast cancer».