A Drug-Drug Interaction Study of Mobocertinib and Midazolam, a Cytochrome P450 3A Substrate, in Patients With Advanced Non-Small Cell Lung Cancer.

Abstract

Mobocertinib is a kinase inhibitor designed to selectively target epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations in non-small cell lung cancer. This drug-drug interaction study assessed the effect of multiple-dose administration of mobocertinib on the pharmacokinetics (PK) of midazolam, a sensitive cytochrome P450 3A substrate. Patients with locally advanced or metastatic non-small cell lung cancer refractory/intolerant to standard available therapy were enrolled. In Cycle 1 (Part A; PK cycle), a single 3-mg oral dose of midazolam was administered on Days 1 and 24, and a single 1-mg intravenous dose of midazolam was administered on Days 2 and 25. Mobocertinib 160 mg once daily was administered orally on Days 3-30. After Cycle 1, patients could continue receiving mobocertinib in 28-day cycles in Part B of the study. The study objective was to characterize the effect of mobocertinib on the single oral- and intravenous-dose PK of midazolam. Safety and exploratory efficacy were also assessed. Twenty-six patients were enrolled, and 13 patients were PK-evaluable. Safety findings were consistent with the known safety profile of mobocertinib, and diarrhea was the only Grade 3 or higher treatment-related adverse event observed in more than 2 patients. Two of 16 patients with EGFR exon 20 insertion mutations were confirmed responders per investigator. Coadministration of mobocertinib decreased the area under the plasma concentration-time curve from time zero to infinity of oral and intravenous midazolam by approximately 32% and 16%, respectively (geometric least-squares mean ratios of 0.676 and 0.837, respectively).