Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: Outcomes and biomarker analysis from the SUMMIT trial Journal Article
| Authors: | Jhaveri, K.; Eli, L. D.; Wildiers, H.; Hurvitz, S. A.; Guerrero-Zotano, A.; Unni, N.; Brufsky, A.; Park, H.; Waisman, J.; Yang, E. S.; Spanggaard, I.; Reid, S.; Burkard, M. E.; Vinayak, S.; Prat, A.; Arnedos, M.; Bidard, F. C.; Loi, S.; Crown, J.; Bhave, M.; Piha-Paul, S. A.; Suga, J. M.; Chia, S.; Saura, C.; Garcia-Saenz, J. Á; Gambardella, V.; de Miguel, M. J.; Gal-Yam, E. N.; Rapael, A.; Stemmer, S. M.; Ma, C.; Hanker, A. B.; Ye, D.; Goldman, J. W.; Bose, R.; Peterson, L.; Bell, J. S. K.; Frazier, A.; DiPrimeo, D.; Wong, A.; Arteaga, C. L.; Solit, D. B. |
| Article Title: | Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: Outcomes and biomarker analysis from the SUMMIT trial |
| 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. © 2023 The Authors |
| Keywords: | adult; controlled study; human tissue; treatment outcome; aged; unclassified drug; gene mutation; human cell; major clinical study; histopathology; cancer growth; diarrhea; drug dose reduction; drug efficacy; drug withdrawal; cancer patient; gene targeting; progression free survival; multiple cycle treatment; phase 2 clinical trial; randomized controlled trial; aromatase inhibitor; cohort analysis; tumor marker; confidence interval; oncogene; dna; blood analysis; drug response; tamoxifen; loperamide; trastuzumab; mammalian target of rapamycin inhibitor; metastatic breast cancer; cyclin dependent kinase inhibitor; erbb2; dna extraction; dna determination; pik3ca gene; fulvestrant; neratinib; tissue preservation; lobular carcinoma; overall response rate; high throughput sequencing; erbb2 gene; her2 gene; hormone receptor-positive; very elderly; dna sequencing; human; male; female; article; circulating tumor dna; cyclin dependent kinase 4 inhibitor; breast ductal carcinoma; her3 gene; cyclin dependent kinase 6 inhibitor; hormone receptor-positive, her2-negative breast cancer; her2-mutant; phosphatidylinositol 4,5 bisphosphate 3 kinase catalytic subunit alpha inhibitor |
| Journal Title: | Annals of Oncology |
| Volume: | 34 |
| Issue: | 10 |
| ISSN: | 0923-7534 |
| Publisher: | Oxford University Press |
| Date Published: | 2023-10-01 |
| Start Page: | 885 |
| End Page: | 898 |
| Language: | English |
| DOI: | 10.1016/j.annonc.2023.08.003 |
| PUBMED: | 37597578 |
| PROVIDER: | scopus |
| PMCID: | PMC11335023 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Komal Jhaveri -- Source: Scopus |
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