Abstract 4336: Translational PK/PD modeling of MEK inhibitors: Trametinib, cobimetinib and binimetinib
Authors: Jake Dickinson, Hitesh B. Mistry
Journal: Cancer Research (2025)

We propose a translational PK/PD framework that enables human dose estimation (HDE), compound ranking and to assess the clinical applicability of cancer cell-line-panels. Translational PK/PD simulations were performed to estimate the efficacious doses in humans. The translational approach was first calibrated using an approved therapy, Trametinib. Cobimetinib and Binimetinib were then used as test compounds. Translational simulations for Cobimetinib and Binimetinib were performed and benchmarked against the Trametinib simulations to aid in HDE. The modelling approach was qualified against reported efficacious doses for Binimetinib and Cobimetinib. The reported population PK (PopPK) models were used to simulate clinical PK. Drug effect was described by an Emax model. in vitro efficacy data for Trametinib, Cobimetinib and Binimetinib, were extracted from the PRISM screen within DepMap Public Access Portal which contained the results of pooled-cell line chemical-perturbation viability screens for 1448 compounds screened against 489 cell lines. EC50 distributions were derived from the PRISM screening for each compound. Only cell-lines that had the same biological profile as the target population, V600E mutated BRAF patients, were included in the EC50 distribution. We have developed a PopPK/PD model structure to simulate the dose-response, where response is the average drug effect (Eavg), by integrating in vitro efficacy cell line data and published PopPK models for MEK-inhibitors Trametinib, Cobimetinib and Binimetinib. Trametinib Eavg at the approved dose, 2mg once daily (QD), was simulated using the developed PopPK/PD model. The simulated median Eavg was 31% and 25th and 75th percentile were 13% and 57% respectively. Dose-response curves, where Eavg was the response, were simulated for Binimetinib and Cobimetinib. A dose that resulted in an Eavg that was matched to the median Trametinib Eavg was identified for both compounds. Expected, efficacious dose was predicted to be 10 mg QD 21/7 (50% Prediction Interval (PI); 6 - 15 mg QD 21/7) for Cobimetinib and 40 mg BID (50% PI; 15 - 95 mg BID) for Binimetinib. To qualify the modelling approach the predicted efficacious doses were compared to the reported maximum tolerable dose (MTD). The predicted efficacious dose for Binimetinib was similar to the reported MTD, 45 mg BID. The predicted efficacious dose for Cobimetinib was slightly lower than MTD, 60 mg QD 21/7. The translational PK/PD framework highlighted that the routine cancer cell-line-panels, in this instance the PRISM assay, may well be suitable for making HDE. The predictions may be improved further by using multiple different in vitro systems and more complex assays. Additionally, the translational framework enables compound ranking and selection and aids in quantifying a clinical therapeutic window. We are thankful for fruitful discussions with Heinrich Huber of Boehringer Ingelheim. Citation Format: Jake Dickinson, Hitesh B. Mistry. Translational PK/PD modeling of MEK inhibitors: Trametinib, cobimetinib and binimetinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4336.