(M-115) Population Pharmacokinetic and Exposure-Response Analyses of Tasurgratinib in Subjects with Unresectable Advanced or Metastatic Cholangiocarcinoma with Fibroblast Growth Factor Receptor 2 Gene Fusion

Maiko Nomoto, Ph.D. – Associate Director, Eisai Co., Ltd., Tokyo, Japan; Setsuo Funasaka, Ph.D. – Associate Director, Eisai Co., Ltd., Tokyo, Japan; Ziad Hussein, Ph.D. – Executive Director, Eisai Ltd., Hatfield, Hertfordshire, UK; Sanae Yasuda, Ph.D. – Executive Director, Eisai Inc., Nutley, New Jersey, USA; Osamu Takenaka, Ph.D. – Senior Director, Eisai Co., Ltd., Tokyo, Japan

Objectives: Tasurgratinib is an oral tyrosine kinase inhibitor that selectively inhibits the kinase activities of fibroblast growth factor receptor (FGFR) 1-3. Population pharmacokinetic (PopPK) analysis was performed to characterize the PK of tasurgratinib and its pharmacologically active metabolite M2 in subjects with cholangiocarcinoma (CCA) and other solid tumors. Exposure-response (E-R) analyses were performed to evaluate the relationships between sum of model-predicted exposure (AUC at steady state [AUC_ss]) of tasurgratinib and M2 and blood biomarkers (phosphate, FGF23 and 1,25-(OH)₂-Vitamin D [DHVD]) or efficacy (objective response and progression free survival), and between model-predicted exposure (AUC_ss or C_max at steady state [C_ss,max]) of tasurgratinib or M2 and safety (treatment-emergent adverse events [TEAEs]).

Methods: Data from two clinical studies (N=93) [1-3] were used for PopPK analysis and E-R analyses for biomarkers and safety, and the data from one of these studies (N=63, CCA only) [3] were used for E-R analysis for efficacy. The PopPK, conducted separately for tasurgratinib and M2, and E-R analyses for biomarkers were performed using NONMEM. The relationships between exposure and efficacy or safety were evaluated graphically.

Results: The PK of tasurgratinib was best described by a 2-compartment model with simultaneous zero and first order absorption and linear elimination from the central compartment. No statistically significant covariates were identified. The PK of M2 was best described by a 2-compartment model with simultaneous zero and first order formation with lag time and linear elimination from the central compartment. Apparent clearance of M2 in subjects with CCA was 41% higher compared to other solid tumors. No other statistically significant covariates were identified. The E-R relationships for phosphate, FGF23 and DHVD were best described by E_max or sigmoid E_max models. No statistically significant covariates were identified in any of the E-R models. At the sum of AUC_ss of tasurgratinib and M2 at the clinical recommended dose of 140 mg once daily (QD), both the increase in phosphate and FGF23 almost reached their model-predicted maximums. However, the increase in DHVD was slightly lower than the model-predicted maximum. There was no clear relationship between sum of AUC_ss of tasurgratinib and M2 and efficacy. Subjects with higher hyperphosphatemia grade tended to have higher tasurgratinib or M2 exposure (AUC_ss or C_ss,max) than those without hyperphosphatemia. No clear relationship was observed for other TEAEs.

Conclusions: The PopPK models described the PK of tasurgratinib and M2 adequately. The E-R models well described the relationships between the sum of AUC_ss of tasurgratinib and M2 and each biomarker. Based on these E-R models, the approximately maximum increase in biomarkers can be expected at the dose of 140 mg QD; which supports the dosage is optimal as clinical recommended dose of tasurgratinib.

Citations: [1] Koyama T, et al. Cancer Sci. 2020;111(2):571-579.
[2] Morizane C, et al. Ann Oncol. 2020;31:S1287-S1318. (Poster)
[3] Furuse J, et al. J Clin Oncol. 2024;42:3_suppl:471. (Poster)