PII-083 - POPULATION PHARMACOKINETIC (POPPK) MODELING OF ENCORAFENIB (ENCO) IN HEALTHY PARTICIPANTS AND PARTICIPANTS WITH BRAF V600-MUTANT SOLID TUMORS IN PHASE 1, 2, AND 3 STUDIES: A SEMIMECHANISTIC AUTOINDUCTION MODEL.

D. Yang¹, E. Hahn², J. Piscitelli³, Y. Pithavala⁴, J. Hibma¹; ¹Pfizer Inc., San Diego, CA, USA, ²Pfizer Inc., Boulder, CO, USA, ³Pfizer, Inc., San Diego, CA, USA, ⁴Pfizer, Inc., San Diego, CA, United States.

Background: ENCO is a potent and selective ATP-competitive inhibitor of B-RAF proto-oncogene, serine/threonine-protein kinase (BRAF) V600-mutant kinase. ENCO is approved for multiple indications in combination with either binimetinib or cetuximab. ENCO exhibits simultaneous time dependent inhibition and induction, with the net effect being autoinduction of CYP3A4, resulting in lower steady state (SS) exposure compared to after a single dose. The goal of this analysis was to develop a global PopPK model to characterize ENCO disposition across multiple tumor types.

Methods: The PopPK analysis was based on 9 Phase 1, 2, and 3 Studies, in participants with melanoma, colorectal cancer (CRC), non-small cell lung cancer, other solid tumors, and healthy participants. In total, 1310 participants were included who received ENCO as monotherapy, or in combination. Non-linear mixed effects modeling approach (NONMEM v 7.5.0) with stochastic approximation expectation-maximization estimation method with interaction was used. A semi-mechanistic enzyme turnover model was assessed to quantify the autoinduction effect. Stepwise covariate modeling evaluated a broad range of covariates (e.g., age, body weight [BWT], and tumor type).

Results: A two-compartment model with first-order absorption and concentration-dependent autoinduction successfully characterized the concentration-time profile of ENCO. ENCO apparent clearance (CL/F) was estimated to be 12.2 L/h after the first dose in a typical adult and increased 186% (to 35 L/h) at SS. This model predicted maximum auto-induction after 14 days in a typical patient. Age and tumor type (metastatic CRC) on CL/F and BWT on volume of distribution were found to be significant covariates, however, these effects were not considered to be clinically significant.

Conclusion: The global ENCO PopPK model, which incorporated a semi-mechanistic enzyme turnover model with concentration-dependent net-autoinduction through an increased enzyme production rate successfully described the PK of ENCO over time and across tumor types. No dose modifications are suggested based on the intrinsic or extrinsic factors evaluated in this analysis.