Phase I Study of Intermittent High-Dose Lapatinib Alternating with Capecitabine for HER2-Positive Breast Cancer Patients with Central Nervous System Metastases

Lapatinib and capecitabine cross the blood-tumor barrier in breast cancer brain metastasis but have modest clinical efficacy. Administration of high-dose tyrosine kinase inhibitor has been evaluated in brain metastases and primary brain tumors as a strategy to improve drug exposure in the central ne...

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Veröffentlicht in:Clinical cancer research 2019-07, Vol.25 (13), p.3784-3792
Hauptverfasser: Morikawa, Aki, de Stanchina, Elisa, Pentsova, Elena, Kemeny, Margaret M, Li, Bob T, Tang, Kendrick, Patil, Sujata, Fleisher, Martin, Van Poznak, Catherine, Norton, Larry, Seidman, Andrew D
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Sprache:eng
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Zusammenfassung:Lapatinib and capecitabine cross the blood-tumor barrier in breast cancer brain metastasis but have modest clinical efficacy. Administration of high-dose tyrosine kinase inhibitor has been evaluated in brain metastases and primary brain tumors as a strategy to improve drug exposure in the central nervous system (CNS). We derived a rational drug scheduling of intermittent high-dose lapatinib alternating with capecitabine based on our preclinical data and Norton-Simon mathematical modeling. We tested this intermittent, sequential drug schedule in patients with breast cancer with CNS metastasis. We conducted a phase I trial using an accelerated dose escalation design in patients with HER2-positive (HER2 ) breast cancer with CNS metastasis. Lapatinib was given on day 1-3 and day 15-17 with capecitabine on day 8-14 and day 22-28 on an every 28-day cycle. Lapatinib dose was escalated, and capecitabine given as a flat dose at 1,500 mg BID. Toxicity and efficacy were evaluated. Eleven patients were enrolled: brain only (4 patients, 36%), leptomeningeal (5 patients, 45%), and intramedullary spinal cord (2 patients, 18%). Grade 3 nausea and vomiting were dose-limiting toxicities. The MTD of lapatinib was 1,500 mg BID. Three patients remained on therapy for greater than 6 months. High-dose lapatinib is tolerable when given intermittently and sequentially with capecitabine. Antitumor activity was noted in both CNS and non-CNS sites of disease. This novel administration regimen is feasible and efficacious in patients with HER2 breast cancer with CNS metastasis and warrants further investigation.
ISSN:1078-0432
1557-3265
1557-3265
DOI:10.1158/1078-0432.CCR-18-3502