Abstract
Systemic lapatinib exposure can be safely increased by intermittent dosing but ultimately plateaus.
Major finding: Systemic lapatinib exposure can be safely increased by intermittent dosing but ultimately plateaus.
Clinical relevance: Higher lapatinib exposure was associated with increased clinical benefit.
Impact: Higher systemic exposure of HER2 inhibitors may be required for near-complete HER2 inactivation.
Despite the existence of potent HER2 tyrosine kinase inhibitors (TKI) such as lapatinib, the effectiveness of HER2 kinase inhibition is limited by compensatory negative feedback signaling that upregulates the oncogenic activity of HER2 in the presence of HER2 inhibitors. Durable inhibition of HER2 signaling can be achieved in vitro with high concentrations of HER2 TKIs that completely inactivate HER2 kinase activity, but continuous administration of high doses of HER2 TKIs leads to intolerable toxicities in vivo. Hypothesizing that intermittent dosing would safely increase lapatinib exposure and thus more effectively inactivate HER2, Chien and colleagues conducted a single-institution phase I dose-escalation trial of intermittent high-dose oral lapatinib therapy in 40 patients with advanced HER2-overexpressing breast cancer. No dose-limiting toxicities were observed at the highest doses; however, steady-state lapatinib plasma concentrations did not increase in a dose-dependent manner and plateaued. Additional cohorts were therefore designed to determine whether food intake, CYP3A4 inhibition, or dose fractionation could increase systemic lapatinib exposure, but only coadminstration of the CYP3A4 inhibitor ketoconazole was found to increase lapatinib exposure. Of 30 patients evaluable after 8 weeks of therapy, 6 had a partial or complete response and 5 had stable disease. There was no correlation between oral lapatinib dose and antitumor activity, but the lapatinib plasma concentration was significantly higher in patients who had a clinical response or stable disease than in those who did not. Among the patients with clinical responses, the most remarkable responses were observed in patients with lapatinib plasma levels approaching the range at which efficacy was observed in preclinical studies. Although a lapatinib exposure ceiling in humans precluded direct testing of the initial hypothesis that intermittent high-dose lapatinib therapy more completely inhibits HER2 than standard dosing, these observations provide support for the development of HER2 TKI formulations or adjuvants that enhance systemic exposure.
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