Rachel A Freedman1, Rebecca S Gelman2, Nathalie Y R Agar3, Sandro Santagata4, Elizabeth C Randall3, Begoña Gimenez-Cassina Lopez3, Roisin M Connolly5, Ian F Dunn6, Catherine H Van Poznak7, Carey K Anders8, Michelle E Melisko9, Kelly Silvestri10, Christine M Cotter10, Kathryn P Componeschi10, Juan M Marte10, Beverly Moy11, Kimberly L Blackwell12, Shannon L Puhalla13, Nuhad Ibrahim14, Timothy J Moynihan15, Julie Nangia16, Nadine Tung17, Robyn Burns18, Mothaffar F Rimawi16, Ian E Krop10, Antonio C Wolff5, Eric P Winer10, Nancy U Lin10. 1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. Electronic address: rafreedman@partners.org. 2. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA. 3. Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA. 4. Department of Pathology, Brigham and Women's Hospital, Boston, MA. 5. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD. 6. Department of Neurosurgery, University of Oklahoma, Oklahoma City, OK. 7. University of Michigan, Ann Arbor, MI. 8. Division of Medical Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC. 9. Department of Medical Oncology, University of California at San Francisco, San Francisco, CA. 10. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. 11. Massachusetts General Hospital, Boston, MA. 12. Department of Medicine, Duke University Medical Center, Durham, NC. 13. University of Pittsburgh Cancer Institute, Magee-Women's Hospital, Pittsburgh, PA. 14. The University of Texas MD Anderson Cancer Center, Houston, TX. 15. Department of Medical Oncology, Mayo Clinic, Rochester, MN. 16. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX. 17. Beth Israel Deaconess Medical Center, Boston, MA. 18. The Emmes Corporation, Rockville, MD.
Abstract
PURPOSE: This 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 METHODS: Patients 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. RESULTS: We 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. CONCLUSION: Neratinib 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.
PURPOSE: This 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 METHODS: Patients 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. RESULTS: We 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. CONCLUSION:Neratinib 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.
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