An Evaluation of the Drug Interaction Potential of Encorafenib in Combination With Binimetinib Using the Inje Cocktail in Patients With Cancer

A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of single and multiple oral doses of encorafenib on the single oral dose pharmacokinetics (PK) of the cytochrome P450 (CYP) enzyme probe substrates, losartan (CYP2C9), midazolam (CYP3A4), caffeine (CYP1A2), omeprazole (CYP2C19), and dextromethorphan (CYP2D6) administered as a cocktail (Inje). This study was conducted, post-approval, in patients with BRAF V600-mutant advanced solid tumors, and aimed to address the remaining uncertainty in the DDI potential of encorafenib as a perpetrator of these CYP enzymes. Study participants received the cocktail on Days -7, 1, and 14 and continuous doses of encorafenib (450 mg q.d.) and binimetinib (45 mg b.i.d.) starting on Day 1. PK sampling and urine collection were conducted from 0 to 8 hours on cocktail administration days. PK parameters were calculated for each participant using noncompartmental analysis of concentration-time data or amount excreted for urine parameters. At steady-state encorafenib plasma concentrations, midazolam plasma C_max and AUC_last decreased by 74% and 82%, respectively. No clinically significant DDIs were observed at encorafenib steady-state concentrations with the other probe substrates of interest. The results from this clinical study indicate that encorafenib is a strong inducer of CYP3A (≥ 80% decrease in midazolam area under the curve (AUC)) at steady state. Based on these results regarding co-administration with encorafenib, sensitive substrates of CYP3A should be avoided or dose adjusted based on the recommendations of their approved product labeling. This information has been included in the updated prescribing information for encorafenib.