Neratinib and ado-trastuzumab emtansine for pretreated and untreated human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases: Translational Breast Cancer Research Consortium trial 022.

Autor:	Freedman RA; Medical Oncology, Dana-Farber Cancer Institute, Boston; Breast Oncology Program, Dana-Farber Cancer Institute, Boston. Electronic address: Rachel_freedman@dfci.harvard.edu., Heiling HM; Department of Data Sciences, Dana-Farber Cancer Institute, Boston, USA., Li T; Department of Data Sciences, Dana-Farber Cancer Institute, Boston, USA., Trapani D; Division of New Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan; Department of Oncology and Hematology, University of Milan, Milan, Italy., Tayob N; Medical Oncology, Dana-Farber Cancer Institute, Boston; Department of Data Sciences, Dana-Farber Cancer Institute, Boston, USA., Smith KL; Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore., Davis R; Medical Oncology, Dana-Farber Cancer Institute, Boston; Breast Oncology Program, Dana-Farber Cancer Institute, Boston., Pereslete AM; Medical Oncology, Dana-Farber Cancer Institute, Boston; Breast Oncology Program, Dana-Farber Cancer Institute, Boston., DeMeo MK; Medical Oncology, Dana-Farber Cancer Institute, Boston; Breast Oncology Program, Dana-Farber Cancer Institute, Boston., Cotter C; Medical Oncology, Dana-Farber Cancer Institute, Boston; Breast Oncology Program, Dana-Farber Cancer Institute, Boston., Chen WY; Medical Oncology, Dana-Farber Cancer Institute, Boston; Breast Oncology Program, Dana-Farber Cancer Institute, Boston., Parsons HA; Medical Oncology, Dana-Farber Cancer Institute, Boston; Breast Oncology Program, Dana-Farber Cancer Institute, Boston., Santa-Maria CA; Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore., Van Poznak C; Department of Internal Medicine, University of Michigan, Ann Arbor., Moy B; Department of Medicine, Division of Hematology/Oncology, Massachusetts General Hospital, Boston., Brufsky AM; Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh., Melisko ME; Division of Hematology and Oncology, University of California at San Francisco, San Francisco., O'Sullivan CC; Medical Oncology, Mayo Clinic, Rochester., Ashai N; Department of Medicine, Georgetown Lombardi Comprehensive Cancer Center and MedStar Health, Washington., Rauf Y; Department of Neurology, University of North Carolina, Chapel Hill., Nangia JR; Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston., Burns RT; Department of Medicine, Yale Cancer Center, New Haven, USA., Savoie J; Medical Oncology, Dana-Farber Cancer Institute, Boston; Breast Oncology Program, Dana-Farber Cancer Institute, Boston., Wolff AC; Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore., Winer EP; Department of Medicine, Yale Cancer Center, New Haven, USA., Rimawi MF; Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston., Krop IE; Department of Medicine, Yale Cancer Center, New Haven, USA., Lin NU; Medical Oncology, Dana-Farber Cancer Institute, Boston; Breast Oncology Program, Dana-Farber Cancer Institute, Boston.
Jazyk:	angličtina
Zdroj:	Annals of oncology : official journal of the European Society for Medical Oncology [Ann Oncol] 2024 Nov; Vol. 35 (11), pp. 993-1002. Date of Electronic Publication: 2024 Jul 06.
DOI:	10.1016/j.annonc.2024.07.245
Abstrakt:	Background: Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. Patients and Methods: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A-previously untreated BCBM, cohorts 4B and 4C-BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed. Results: Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months. Conclusions: We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated. (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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