Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial

• DOI: 10.1016/j.annonc.2023.08.003
• Publication Date: 2023-08-18T11:47:34Z
• Authors: K. Jhaveri; L.D. Eli; H. Wildiers; S.A. Hurvitz; A. Guerrero-Zotano; N. Unni; A. Brufsky; H. Park; J. Waisman; E.S. Yang; I. Spanggaard; S. Reid; M.E. Burkard; S. Vinayak; A. Prat; M. Arnedos; F.-C. Bidard; S. Loi; J. Crown; M. Bhave; S.A. Piha-Paul; J.M. Suga; S. Chia; C. Saura; J.Á. Garcia-Saenz; V. Gambardella; M.J. de Miguel; E.N. Gal-Yam; A. Raphael; S.M. Stemmer; C. Ma; A.B. Hanker; D. Ye; J.W. Goldman; R. Bose; L. Peterson; J.S.K. Bell; A. Frazier; D. DiPrimeo; A. Wong; C.L. Arteaga; D.B. Solit
• Keywords: Receptor, ErbB-2; ICTS (Institute of Clinical and Translational Sciences); 610; [SDV.CAN]Life Sciences [q-bio]/Cancer; Breast Neoplasms; Trastuzumab; Article; 3. Good health; neratinib; ErbB-2; Antineoplastic Combined Chemotherapy Protocols; Medicine and Health Sciences; Humans; hormone receptor-positive; Female; metastatic breast cancer; HER2-mutant; ERBB2; Fulvestrant; Receptor

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 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.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.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.