PII-046 - AN EVALUATION OF THE DRUG INTERACTION POTENTIAL OF ENCORAFENIB IN COMBINATION WITH BINIMETINIB USING THE INJE COCKTAIL IN PATIENTS WITH BRAF V600-MUTANT UNRESECTABLE OR METASTATIC MELANOMA OR OTHER ADVANCED SOLID TUMORS

J. Piscitelli¹, M. Reddy¹, L. Wollenberg¹, L. Del Frari², J. Gong¹, K. Matschke³, J. Williams¹; ¹Pfizer, Inc., ²Pierre Fabre Medicament, ³Pfizer, Inc., Collegeville, PA, USA.

Background: Encorafenib in combination with binimetinib or cetuximab is indicated for patients with unresectable or metastatic melanoma or metastatic colorectal cancer, respectively, with selected BRAF V600 mutations. In vitro studies indicated encorafenib was a potential inhibitor of CYP1A2, CYP2C9, CYP2D6, and CYP3A4/5, and also a time-dependent inhibitor of CYP3A4. Additionally, encorafenib induced CYP2C9 and CYP3A4 in human primary hepatocytes. In vivo, CYP3A4 substrate encorafenib in an autoinducer based on lower exposures at steady state compared to Day 1. The current clinical study was designed to evaluate the effect of encorafenib in combination with binimetinib on the single oral dose PK of the specific CYP substrates included in the Inje Cocktail. This cocktail was selected as it includes losartan (CYP2C9), midazolam (CYP3A4), caffeine (CYP1A2), and dextromethorphan (CYP2D6), which are all CYP substrates of interest to coadministration with encorafenib, along with omeprazole (CYP2C19).

Methods: This was an open-label, fixed-sequence study conducted in patients with BRAF V600-mutant unresectable or metastatic melanoma or other advanced solid tumors. Patients received a single oral dose of the Inje cocktail on Day -7, Day 1 and Day 14. Encorafenib 450 mg QD and binimetinib 45 mg BID were administered starting on Day 1. PK sampling and urine collection were conducted from 0 to 8 hours on Day -7, Day 1 and Day 14. Exposure parameters were calculated for each patient by noncompartmental analysis (or amount excreted for urine parameters) and geometric least-squares mean ratio and corresponding 90% confidence intervals (CI) were calculated to estimate the magnitude of effects.

Results: A summary of the analysis of the PK parameters for each of the Inje CYP probe substrates at single dose and steady-state encorafenib concentrations is presented in Table 1.

Conclusion: The results from this clinical study indicate encorafenib is a strong inducer of CYP3A. Based on these results, sensitive substrates of CYP3A should be avoided or dose-adjusted based on the recommendations of their approved product labeling. No clinically significant DDI was observed at encorafenib steady-state plasma concentrations with omeprazole (CYP2C19), caffeine (CYP1A2), losartan (CYP2C9) or dextromethorphan (CYP2D6).