open access publication

Article, 2023

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

ANNALS OF ONCOLOGY, ISSN 0923-7534, 0923-7534, Volume 34, 10, Pages 885-898, 10.1016/j.annonc.2023.08.003

Contributors

Jhaveri, K. (Corresponding author) [1] [2] [3] Eli, L. D. [4] Wildiers, H. [5] [6] Hurvitz, S. A. [7] [8] [9] [10] Guerrero-Zotano, A. [11] Unni, N. [12] [13] Brufsky, A. [14] [15] Park, H. [16] Waisman, J. [17] Yang, E. S. [18] [19] Spanggaard, I. [20] [21] Reid, S. [22] Burkard, M. E. [23] [24] Vinayak, S. [25] Prat, A. [26] [27] Arnedos, M. [28] [29] Bidard, F. -C. [29] [30] [31] [32] Loi, S. [33] [34] [35] Crown, J. [36] [37] Bhave, M. [38] Piha-Paul, S. A. [12] [39] Suga, J. M. [40] Chia, S. [41] Saura, C. [42] [43] Garcia-Saenz, J. a. [44] [45] [46] Gambardella, V. [47] de Miguel, M. J. [48] Gal-Yam, E. N. [49] Raphael, A. [50] [51] Stemmer, S. M. [52] [53] Ma, C. [16] [54] Hanker, A. B. [12] [13] Ye, D. [12] [13] Goldman, J. W. [55] Bose, R. [16] [54] Peterson, L. [16] [54] Bell, J. S. K. [56] Frazier, A. [4] Diprimeo, D. [4] Wong, A. [4] Arteaga, C. L. [12] [13] Solit, D. B. [3]

Affiliations

  1. [1] Weill Cornell Med Coll, New York, NY USA
    2. [NORA names: United States; America, North; OECD];
  2. [2] Weill Cornell Med Coll, New York, NY USA
    3. [NORA names: United States; America, North; OECD];
  3. [3] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY USA
    4. [NORA names: United States; America, North; OECD];
  4. [4] Clin Dev, Puma Biotechnol, Los Angeles, CA USA
    5. [NORA names: United States; America, North; OECD];
  5. [5] Univ Hosp Leuven, Leuven, Belgium
    6. [NORA names: Belgium; Europe, EU; OECD];

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.

Keywords

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

Data Provider: Clarivate

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