PI-061 - EFFECT OF A MODERATE CYP3A4 INDUCER ON ENCORAFENIB IN COMBINATION WITH BINIMETINIB IN PATIENTS WITH BRAF V600-MUTANT UNRESECTABLE OR METASTATIC MELANOMA OR OTHER ADVANCED SOLID TUMORS.

J. Piscitelli¹, M. Reddy², J. Gong³, K. Matschke⁴, A. Fomin¹, J. Williams¹; ¹Pfizer, San Diego, CA, USA, ²Pfizer, Boulder, CO, USA, ³Pfizer, New York, NY, USA, ⁴Pfizer, 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 data indicated that encorafenib is mainly metabolized by CYP3A4, making encorafenib susceptible to DDI when coadministered with CYP inhibitors or inducers (in addition to auto-induction of CYP3A4 after multiple encorafenib doses). The current clinical study was designed to evaluate the effect of multiple doses of modafinil, a moderate CYP3A4 inducer when administered at 400 mg, on the multiple oral dose PK of encorafenib and its metabolite, LHY746, in advanced cancer patients.

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. Treatment of 400 mg QD modafinil was given on Day 15 through Day 21. Encorafenib 450 mg QD and binimetinib 45 mg BID were administered starting on Day 1. PK sampling was conducted from 0 to 8 hours on Day 14 and Day 21. Exposure parameters were calculated for each patient by noncompartmental analysis and geometric least-squares mean ratio. Corresponding 90% confidence intervals were calculated to estimate the magnitude of effects.

Results: Among 10 PK evaluable patients, encorafenib Cmax and AUClast were decreased in presence of steady-state modafinil by approximately 30%. LHY746 exposures were not substantially changed in the presence of steady-state modafinil.

Conclusion: The results from this clinical study indicate modafinil had a mild effect on encorafenib PK. Based on these results, encorafenib can be coadministered with a moderate CYP3A4 inducer without dosing adjustment.