Neratinib + Fulvestrant + Trastuzumab for HR-Positive, HER2-Negative, HER2-Mutant Metastatic Breast Cancer: Outcomes and Biomarker Analysis From the SUMMIT Trial

Annals of Oncology Manuscript
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. Rapael, 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


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 (7 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 CDK4/6 inhibitor therapy received N+F+T (oral neratinib 240 mg/d with loperamide prophylaxis, intramuscular fulvestrant 500 mg days 1, 15, 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 crossover 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%CI 26–52); median PFS was 8.3 months (95% CI 6.0–15.1). 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 ctDNA 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 CDK4/6 inhibitors is clinically meaningful and, based on this study, N+F+T has been included in National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.