Journal article
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, Vol.34(10), pp.885-898
10/01/2023
DOI: 10.1016/j.annonc.2023.08.003
PMCID: PMC11335023
PMID: 37597578
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.
Details
- Title: Subtitle
- Neratinib plus fulvestrant plus trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial
- Creators
- K. Jhaveri - Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY USAL. D. Eli - Clin Dev, Puma Biotechnol, Los Angeles, CA USAH. Wildiers - Univ Hosp Leuven, Leuven, BelgiumS. A. Hurvitz - David Geffen Sch Med, UCLA, Santa Monica, CA USAA. Guerrero-Zotano - Fdn Inst Valenciano Oncol, Med Oncol Dept, Valencia, SpainN. Unni - UT Southwestern Med Ctr, Dallas, TX USAA. Brufsky - UPMC, Magee Womens Hosp, Pittsburgh, PA USAH. Park - Washington Univ, Sch Med, St Louis, MO USAJ. Waisman - City Of Hope National Medical CenterE. S. Yang - University of AlabamaI. Spanggaard - Rigshosp, Copenhagen Univ Hosp, Dept Oncol, Copenhagen, DenmarkS. Reid - Vanderbilt Ingram Canc Ctr, Div Hematol Oncol Breast Oncol, Breast Canc Program, Med Ctr, Nashville, TN USAM. E. Burkard - Univ Wisconsin, Dept Med, Div Hematol Oncol, Sch Med & Publ Hlth, Madison, WI USAS. Vinayak - Seattle Canc Care Alliance, Seattle, WA USAA. Prat - Hosp Clin Barcelona, Barcelona, SpainM. Arnedos - Dept Med Oncol, Gustave Roussy, Villejuif, FranceF. -C. Bidard - Institut CurieS. Loi - Peter MacCallum Canc Ctr, Div Canc Res, Melbourne, EnglandJ. Crown - St Vincents Univ Hosp, Dublin, IrelandM. Bhave - Emory UniversityS. A. Piha-Paul - Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX USAJ. M. Suga - Kaiser PermanenteS. Chia - Dept Med Oncol, British Columbia Canc Agcy, Vancouver, BC, CanadaC. Saura - Vall dHebron Univ Hosp, Vall dHebron Inst Oncol VHIO, Med Oncol Serv, Barcelona, SpainJ. a. Garcia-Saenz - Instituto de Investigación Sanitaria del Hospital Clínico San CarlosV. Gambardella - Hosp Clin Valencia, Inst Invest Sanitaria INCL, Valencia, SpainM. J. de Miguel - StartE. N. Gal-Yam - Inst Breast Oncol, Sheba Med Ctr, Ramat Gan, IsraelA. Raphael - Sourasky Med Ctr, Tel Aviv, IsraelS. M. Stemmer - Davidoff Canc Ctr, Rabin Med Ctr, Petah Tiqwa, IsraelC. Ma - Washington Univ, Dept Med, Div Med Oncol, St Louis, MO USAA. B. Hanker - UT Southwestern, Simmons Comprehens Canc Ctr, Dallas, TX USAD. Ye - UT Southwestern, Simmons Comprehens Canc Ctr, Dallas, TX USAJ. W. Goldman - UCLA Hematol & Oncol, Santa Monica, CA USAR. Bose - Washington Univ, Dept Med, Div Med Oncol, St Louis, MO USAL. Peterson - Washington Univ, Dept Med, Div Med Oncol, St Louis, MO USAJ. S. K. Bell - Tempus LabsA. Frazier - Clin Dev, Puma Biotechnol, Los Angeles, CA USAD. Diprimeo - Clin Dev, Puma Biotechnol, Los Angeles, CA USAA. Wong - Clin Dev, Puma Biotechnol, Los Angeles, CA USAC. L. Arteaga - Southwestern Medical CenterD. B. Solit - Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY USA
- Resource Type
- Journal article
- Publication Details
- Annals of oncology, Vol.34(10), pp.885-898
- Publisher
- Elsevier
- DOI
- 10.1016/j.annonc.2023.08.003
- PMID
- 37597578
- PMCID
- PMC11335023
- ISSN
- 0923-7534
- eISSN
- 1569-8041
- Number of pages
- 14
- Grant note
- Puma Biotechnology, Inc. Breast Cancer Research Foundation, New York, NY, USA National Breast Cancer Foundation of Australia Endowed Chair P30CA014520 / Carbone Cancer Center, University of Wisconsin-Madison P30-CA008748 / Memorial Sloan Kettering Cancer Center under the NCI Cancer Center R01CA224899 / NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 10/01/2023
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984701253102771
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