Phase i study of intermittent high-dose lapatinib alternating with capecitabine for HER2-positive breast cancer patients with central nervous system metastases

Aki Morikawa, Elisa De Stanchina, Elena Pentsova, Margaret M. Kemeny, Bob T. Li, Kendrick Tang, Sujata Patil, Martin Fleisher, Catherine Van Poznak, Larry Norton, Andrew D. Seidman

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Purpose: 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. Patients and Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)3784-3792
Number of pages9
JournalClinical Cancer Research
Volume25
Issue number13
DOIs
StatePublished - 2019
Externally publishedYes

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