Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial
- Author(s)
- Jhaveri, K; Eli, LD; Wildiers, H; Hurvitz, SA; Guerrero-Zotano, A; Unni, N; Brufsky, A; Park, H; Waisman, J; Yang, ES; Spanggaard, I; Reid, S; Burkard, ME; Vinayak, S; Prat, A; Arnedos, M; Bidard, FC; Loi, S; Crown, J; Bhave, M; Piha-Paul, SA; Suga, JM; Chia, S; Saura, C; Garcia-Saenz, JA; Gambardella, V; de Miguel, MJ; Gal-Yam, EN; Rapael, A; Stemmer, SM; Ma, C; Hanker, AB; Ye, D; Goldman, JW; Bose, R; Peterson, L; Bell, JSK; Frazier, A; DiPrimeo, D; Wong, A; Arteaga, CL; Solit, DB;
- Details
- Publication Year 2023-10,Volume 34,Issue #10,Page 885-898
- Journal Title
- Annals of Oncology
- Publication Type
- Research article
- Abstract
- BACKGROUND: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T. PATIENTS AND METHODS: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing. RESULTS: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 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 and lobular histology, 1 or >/=1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response. CONCLUSIONS: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.
- Publisher
- Elsevier
- Keywords
- Erbb2; HER2-mutant; hormone receptor-positive; metastatic breast cancer; neratinib
- Department(s)
- Laboratory Research; Medical Oncology
- PubMed ID
- 37597578
- Publisher's Version
- https://doi.org/10.1016/j.annonc.2023.08.003
- Open Access at Publisher's Site
https://doi.org/10.1016/j.annonc.2023.08.003- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-10-31 06:07:53
Last Modified: 2023-10-31 06:08:17