Abstract
e11077 Background: The highly effective treatment of HER2-amplified BC has proven challenging due to signal buffering capacity inherent in the functionally relevant HER2-HER3 target. HER2-HER3 signaling can be inactivated by doses of Lp that fully inactivate the HER2 kinase. In mouse models, such doses are not tolerable in continuous administration, but are tolerable and highly effective in intermittent dosing. We have begun the clinical translation of this treatment strategy. Methods: We conducted a phase 1 dose-escalation study of a 5-day course of Lp in women with advanced HER2-overexpressing BC. Lp was administered with anti-diarrheal prophylaxis on days 1-5 of a 14 day cycle. Dose escalation was conducted in cohorts of 3 per standard 3+3 design with plasma Lp level monitoring, rigorous cardiac assessment, and exploratory tumor pharmacodynamic studies. Results: 29 patients (pts) have been enrolled to date and 26 are evaluable for toxicity. Lp has been evaluated across doses ranging from 1750 mg/day up to 7000 mg/day in twice-daily dosing. No dose-limiting toxicities, grade 4 or serious adverse events (AEs) were noted. Three pts experienced grade 3 diarrhea. Other common AEs included grade 1 and 2 diarrhea (19 pts), nausea (14 pts), fatigue (13 pts), rash (11pts). Plasma Lp concentrations varied considerably among pts and plateaued with increasing oral dose, failing to achieve the target plasma concentrations associated with high efficacy in preclinical models. Four pts had a partial response, 7 pts had a transient 5-day response, and 2 patients had stable disease for greater than 6 months. These responses were related to systemic exposure. In an attempt to break through the pharmacokinetic ceiling, current cohorts are evaluating exposure-enhancing strategies including the food-effect, inhibition of CYP3A4, and further dose fractionation. Conclusions: Lp dose and exposure can be safely and significantly increased through intermittent dosing but reach a bioavailability ceiling that currently precludes effective translation of the treatment hypothesis. Ongoing cohorts are pursuing novel pharmacokinetic approaches to enhance Lp exposure.
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