Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022.
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.
['Freedman|Rachel A|RA|', 'Gelman|Rebecca S|RS|', 'Agar|Nathalie Y R|NYR|', 'Santagata|Sandro|S|', 'Randall|Elizabeth C|EC|', 'Gimenez-Cassina Lopez|Begoña|B|', 'Connolly|Roisin M|RM|', 'Dunn|Ian F|IF|', 'Van Poznak|Catherine H|CH|', 'Anders|Carey K|CK|', 'Melisko|Michelle E|ME|', 'Silvestri|Kelly|K|', 'Cotter|Christine M|CM|', 'Componeschi|Kathryn P|KP|', 'Marte|Juan M|JM|', 'Moy|Beverly|B|', 'Blackwell|Kimberly L|KL|', 'Puhalla|Shannon L|SL|', 'Ibrahim|Nuhad|N|', 'Moynihan|Timothy J|TJ|', 'Nangia|Julie|J|', 'Tung|Nadine|N|', 'Burns|Robyn|R|', 'Rimawi|Mothaffar F|MF|', 'Krop|Ian E|IE|', 'Wolff|Antonio C|AC|', 'Winer|Eric P|EP|', 'Lin|Nancy U|NU|', '|||']
D000284:Administration, Oral D000328:Adult D000971:Antineoplastic Combined Chemotherapy Protocols D001921:Brain D001932:Brain Neoplasms D001940:Breast D001943:Breast Neoplasms D017024:Chemotherapy, Adjuvant D003399:Craniotomy D004334:Drug Administration Schedule D005260:Female D006801:Humans D008875:Middle Aged D020360:Neoadjuvant Therapy D010865:Pilot Projects D011804:Quinolines D018719:Receptor, ErbB-2 D014018:Tissue Distribution D016896:Treatment Outcome
Metastatic Central nervous system