• Rachel A Freedman, Rebecca S Gelman, AgarNathalie Y RNYRDepartment of Neurosurgery, Brigham and Women's Hospital, Boston, MA., Sandro Santagata, Elizabeth C Randall, Begoña Gimenez-Cassina Lopez, Roisin M Connolly, Ian F Dunn, Catherine H Van Poznak, Carey K Anders, Michelle E Melisko, Kelly Silvestri, Christine M Cotter, Kathryn P Componeschi, Juan M Marte, Beverly Moy, Kimberly L Blackwell, Shannon L Puhalla, Nuhad Ibrahim, Timothy J Moynihan, Julie Nangia, Nadine Tung, Robyn Burns, Mothaffar F Rimawi, Ian E Krop, Antonio C Wolff, Eric P Winer, Nancy U Lin, and Translational Breast Cancer Research Consortium (TBCRC).
• Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. Electronic address: rafreedman@partners.org.
• Clin. Breast Cancer. 2020 Apr 1; 20 (2): 145-151.e2.

PurposeThis pilot study was performed to test our ability to administer neratinib monotherapy before clinically recommended craniotomy in patients with HER2-positive metastatic breast cancer to the central nervous system, to examine neratinib's central nervous system penetration at craniotomy, and to examine postoperative neratinib maintenance.Patients And MethodsPatients with HER2-positive brain metastases undergoing clinically indicated cranial resection of a parenchymal tumor received neratinib 240 mg orally once a day for 7 to 21 days preoperatively, and resumed therapy postoperatively in 28-day cycles. Exploratory evaluations of time to disease progression, survival, and correlative tissue, cerebrospinal fluid (CSF), and blood-based analyses examining neratinib concentrations were planned. The study was registered at ClinicalTrials.gov under number NCT01494662.ResultsWe enrolled 5 patients between May 22, 2013, and October 18, 2016. As of March 1, 2019, patients had remained on the study protocol for 1 to 75+ postoperative cycles pf therapy. Two patients had grade 3 diarrhea. Evaluation of the CSF showed low concentrations of neratinib; nonetheless, 2 patients continued to receive therapy without disease progression for at least 13 cycles, with one on-study treatment lasting for nearly 6 years. Neratinib distribution in surgical tissue was variable for 1 patient, while specimens from 2 others did not produce conclusive results as a result of limited available samples.ConclusionNeratinib resulted in expected rates of diarrhea in this small cohort, with 2 of 5 patients receiving the study treatment for durable periods. Although logistically challenging, we were able to test a limited number of CSF- and parenchymal-based neratinib concentrations. Our findings from resected tumor tissue in one patient revealed heterogeneity in drug distribution and tumor histopathology.Copyright © 2019 Elsevier Inc. All rights reserved.

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