The Phase II MutHER Study of Neratinib Alone and in Combination with Fulvestrant in HER2-Mutated, Non-amplified Metastatic Breast CancerNeratinib and Fulvestrant in HER2-Mutated Breast Cancer
PURPOSE: HER2 mutations (HER2mut) induce endocrine resistance in estrogen receptor-positive (ER+) breast cancer. PATIENTS AND METHODS: In this single-arm multi-cohort phase II trial, we evaluated the efficacy of neratinib plus fulvestrant in patients with ER+/HER2mut, HER2 non-amplified metastatic breast cancer (MBC) in the fulvestrant-treated (n = 24) or fulvestrant-naïve cohort (n = 11). Patients with ER-negative (ER-)/HER2mut MBC received neratinib monotherapy in an exploratory ER- cohort (n = 5). RESULTS: The clinical benefit rate [CBR (95% confidence interval)] was 38% (18%-62%), 30% (7%-65%), and 25% (1%-81%) in the fulvestrant-treated, fulvestrant-naïve, and ER- cohorts, respectively. Adding trastuzumab at progression in 5 patients resulted in three partial responses and one stable disease ≥24 weeks. CBR appeared positively associated with lobular histology and negatively associated with HER2 L755 alterations. Acquired HER2mut were detected in 5 of 23 patients at progression. CONCLUSIONS: Neratinib and fulvestrant are active for ER+/HER2mut MBC. Our data support further evaluation of dual HER2 blockade for the treatment of HER2mut MBC.
Authors
- Ron Bose (ORCID: https://orcid.org/0000-0003-1977-8894)
- P. Kelly Marcom (ORCID: https://orcid.org/0000-0001-5302-6368)
- Julie R. Nangia (ORCID: https://orcid.org/0000-0002-8326-2254)
- Alshad S. Lalani (ORCID: https://orcid.org/0000-0003-4891-9983)
- Feng Gao (ORCID: https://orcid.org/0000-0002-1425-1623)
- Matthew P. Goetz (ORCID: https://orcid.org/0000-0002-4383-270X)
- Brittney Haas (ORCID: https://orcid.org/0000-0002-7488-2849)
- Frances Valdez-Albini
- Shana Thomas (ORCID: https://orcid.org/0000-0002-2381-9997)
- Jason M. Jones (ORCID: https://orcid.org/0000-0001-6460-8427)
- Mark D. Pegram (ORCID: https://orcid.org/0000-0002-9743-8118)
- Janice Lu (ORCID: https://orcid.org/0009-0006-8926-6367)
- Jingqin Luo (ORCID: https://orcid.org/0000-0003-2759-3072)
- Timothy Pluard (ORCID: https://orcid.org/0000-0002-3640-3077)
- Melody Cobleigh (ORCID: https://orcid.org/0000-0001-6385-4693)
- Nancy U. Lin (ORCID: https://orcid.org/0000-0003-2263-5413)
- Lisa A. Carey (ORCID: https://orcid.org/0000-0003-2388-4649)
- Matthew J. Ellis (ORCID: https://orcid.org/0000-0002-8467-8534)
- Gretchen Kimmick (ORCID: https://orcid.org/0000-0001-7096-9624)
- Leslie Bucheit (ORCID: https://orcid.org/0000-0001-8826-0357)
- Jill Anderson
- Eric P. Winer (ORCID: https://orcid.org/0000-0002-8819-1723)
- Cynthia X. Ma
- Rachel A. Freedman (ORCID: https://orcid.org/0000-0003-0460-674X)
- Richard Bryce (ORCID: https://orcid.org/0000-0002-1507-9650)
Institutions
- University of North Carolina at Chapel Hill (US)
Publication Details
- Journal
- UNC Libraries
- Published
- 2025-01-23
- DOI
- https://doi.org/10.17615/kd1v-9129
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- Pfizer
- AstraZeneca
- Genomic Health
- Alvin J. Siteman Cancer Center
- Veracyte
- Puma Biotechnology
- Genentech
- Foundation Medicine