Investigators Attempt to Increase Lapatinib Exposure Through Intermittent Dosing in HER2-Positive Breast Cancer
HER3 links with HER2 in a reciprocal relationship including negative feedback signaling that can upregulate HER2-HER3 signaling to compensate for HER2 inhibition. This signal-buffering capacity protects HER2-HER3 against a nearly 2-log inhibition of HER2 catalytic activity. The anti-HER2 tyrosine kinase inhibitor lapatinib (Tykerb) can inactivate HER2/HER3 signaling at doses that completely inactivate the HER2 kinase; in mouse models such doses are not tolerable when given continuously but are tolerable and effective when given intermittently.
In a phase I dose-escalation study reported in the Journal of Clinical Oncology, Chien et al examined whether intermittent dosing of lapatinib could allow delivery of higher doses and achievement of higher plasma concentrations in women with HER2-overexpressing breast cancer.
Exposure Plateau at High Doses
The study included 40 women with advanced HER2-overexpressing breast cancer who received lapatinib on days 1 through 5 of repeating 14-day cycles at doses of 1,750 to 7,000 mg/d in divided doses. The lapatinib dose was escalated to 7,000 mg/d with no dose-limiting toxicities. However, steady-state lapatinib plasma concentrations did not increase proportionally with increasing lapatinib oral dose. Rather, lapatinib plasma levels plateaued in this dose range, with no increases in exposure being observed at doses greater than 3,000 mg/d.
Attempts to increase lapatinib exposure were made in additional cohorts receiving 3,000 mg/d through use of food effect, CYP3A4 inhibition, and dose fractionation. Among these measures, only coadministration with the CYP3A4 inhibitor ketoconazole increased lapatinib exposure (approximately 2.7-fold increase), although lapatinib bioavailability was highly variable.
Striking Responses at High Plasma Levels
No intolerable exposure levels were observed. Eight patients (20%) experienced grade 3 diarrhea. Six patients achieved a response. The most striking responses were seen in the three patients who achieved lapatinib plasma concentrations approaching 10,000 ng/mL.
One patient had complete and rapid resolution of a 2.6-cm liver metastasis after 2 months of treatment, and another had a complete response in bulky mediastinal metastases lasting almost 1 year; both of these patients had shown disease progression on prior trastuzumab (Herceptin) and standard lapatinib in the metastatic setting. The third patient had a 63% reduction in a lung metastasis lasting 17 months. No evidence of biologic activity of lapatinib was observed in the 10 patients with lapatinib plasma concentrations of ≤ 3,500 ng/mL, with all having progressive disease at 2 months.
The investigators concluded, “Lapatinib exposure can be safely and significantly increased through intermittent dosing but reaches a ceiling that currently impedes clinical translation of the treatment hypothesis. Preliminary efficacy data suggest that exposures approaching those seen in mouse models can result in highly significant tumor responses.”
A. Jo Chien, MD, of Helen Diller Family Comprehensive Cancer Center, San Francisco, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by awards from the California Breast Cancer Research Program, American Society of Clinical Oncology, and American Cancer Society. For full disclosures of the study authors, visit jco.ascopubs.org.
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