Integration of pharmacokinetics, safety, and efficacy into model-informed dose selection for Pimicotinib
Authors: Nie Jing , Li Hui , Shi Haosong , Liu Yi 
Published: February 2025

Objectives: Pimicotinib is an oral, highly potent and selective small-molecule antagonist of CSF-1R with minimum inhibition of c-Kit and PDGFR, currently being developed as an anti-cancer therapy for patients (pts) with Tenosynovial Giant Cell Tumor (TGCT), a rare type of locally aggressive neoplasm primarily caused by the overexpression of the CSF-1 gene[1]. The aim of this analysis was to develop a popPK model to identify intrinsic/extrinsic factors significantly contributing to the PK behavior of Pimicotinib. Additionally, exposure-response (E-R) analysis was performed to depict the relationship between Pimicotinib exposure and efficacy/safety endpoints, ultimately supporting dose selection in further clinical development in TGCT pts. Methods: A popPK model was built to depict the PK behavior of Pimicotinib, considering the impact of baseline factors. The popPK model was developed based on data (n=103) from a Phase I study conducted in US and China, including an escalation phase on solid tumor pts who received oral Pimicotinib at QD doses of 25 mg, 50 mg, 75 mg and 100 mg and expansion cohorts of pts with TGCT (25 mg QD, 50 mg QD) and other tumors (50 mg QD). Using data from TGCT expansion cohorts (n=35), E-R analysis was performed using logistic regression to explore the relationship between Pimicotinib exposure parameters derived from the popPK model and selected response endpoints. Efficacy endpoint was ORR by IRC assessment at week13 and safety endpoints were treatment related adverse events (TRAE) (incidence≥20%) within week13. Results: A 2-cmt model with 1st-order absorption and 1st-order elimination depicts the PK behavior of Pimicotinib. Based on the base model, the effects of baseline factors (bodyweight, age, gender, ethnicity, tumor type, AST, ALT, etc.) on PK were investigated. Age was considered as a significant covariate affecting V2/F. Bodyweight was a significant covariate affecting V3/F. The PK of pts with extreme bodyweight and age was also predicted by simulation, and difference of point estimation was less than 30%, further suggests no needs for dose adjust based on above factors. Based on E-R analysis, similar ORR by IRC (week 13) were found for the upper exposure quartiles but lower ORR at the 1st exposure quartile, suggesting consistent responses across the exposure range achieved with the 50 mg dose with advantage to 25 mg. From safety aspect, within 13 weeks, the incidence rate of treatment related LDH, α-HBDH and CPK increase was positive correlated with exposure. The incidence rate of treatment-related AST, ALT elevation and edema showed a positive trend with exposure. However, most of these AEs were G1/2, manageable and reversible. Conclusions: Pimicotinib PopPK and E-R relationships for efficacy and safety were characterized. These models are being used to identify the optimal Pimicotinib dosing and supported the selection of 50 mg QD as the recommended dose for further development of TGCT indication globally.Citations: [1] Cannarile MA, et al. J Immunother Cancer. 2017; 5(1):53.