Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Annals of Oncology Année : 2023

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

Komal L. Jhaveri
  • Fonction : Auteur
Lisa Diamond Eli
  • Fonction : Auteur
Hans P.M.W. Wildiers
  • Fonction : Auteur
Sara Alsterlind Hurvitz
  • Fonction : Auteur
Ángel L. Guerrero-Zotano
Nisha Unni
  • Fonction : Auteur
Adam M. Brufsky
Haeseong Park
James Ross Waisman
  • Fonction : Auteur
E. S. Yang
  • Fonction : Auteur
Iben Spanggaard
  • Fonction : Auteur
Sonya A. Reid
  • Fonction : Auteur
Mark E. Burkard
Shaveta Vinayak
  • Fonction : Auteur
Aleix Prat
Mónica Arnedos
  • Fonction : Auteur
Sherene M. Loi
  • Fonction : Auteur
John P.A. Crown
  • Fonction : Auteur
Manali Ajay Bhave
  • Fonction : Auteur
S. A. Piha-Paul
Jennifer Marie Suga
  • Fonction : Auteur
Stephen K.L. Chia
  • Fonction : Auteur
Cristina Bandín Saura
  • Fonction : Auteur
José Ángel Garcia-Saenz
  • Fonction : Auteur
Valentina Gambardella
María José de Miguel
  • Fonction : Auteur
Einav Nili Gal-Yam
  • Fonction : Auteur
A. Rapael
  • Fonction : Auteur
Salomon Marcello Stemmer
  • Fonction : Auteur
Cynthia X. Ma
  • Fonction : Auteur
Ariella B. Hanker
Dan Ye
  • Fonction : Auteur
Jonathan Wade Goldman
  • Fonction : Auteur
Ron Bose
  • Fonction : Auteur
Lindsay L. Peterson
Joshua S.K. Bell
  • Fonction : Auteur
A. Frazier
  • Fonction : Auteur
Daniel Diprimeo
  • Fonction : Auteur
Andrea Li Ann Wong
  • Fonction : Auteur
Carlos L. Arteaga
  • Fonction : Auteur
David B. Solit

Résumé

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.

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Cancer
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hal-04229497 , version 1 (06-10-2023)

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Komal L. Jhaveri, Lisa Diamond Eli, Hans P.M.W. Wildiers, Sara Alsterlind Hurvitz, Ángel L. Guerrero-Zotano, et al.. Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial. Annals of Oncology, 2023, 34 (10), pp.885-898. ⟨10.1016/j.annonc.2023.08.003⟩. ⟨hal-04229497⟩
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