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

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. BhaveS. A. Piha-Paul, J. M. Suga, S. Chia, C. Saura, J. 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

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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.

Original languageEnglish
Pages (from-to)885-898
Number of pages14
JournalAnnals of Oncology
Issue number10
StatePublished - Oct 2023

Bibliographical note

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© 2023 The Authors


  • ERBB2
  • HER2-mutant
  • hormone receptor-positive
  • metastatic breast cancer
  • neratinib

ASJC Scopus subject areas

  • Hematology
  • Oncology


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