1175P - Pharmacokinetics of ensartinib in advanced solid tumors and anaplastic lymphoma kinase-positive non-small cell lung cancer

Background

Ensartinib is a novel and potent anaplastic lymphoma kinase (ALK) inhibitor. This study aimed to develop a population pharmacokinetic (POP-PK) model for ensartinib in advanced solid tumors and ALK-positive non–small cell lung cancer (NSCLC) and to investigate the exposure-response (E-R) and dose-response (D-R) relationships for selected efficacy and safety endpoints.

Methods

Population PK modeling was conducted in nonlinear mixed-effects modeling software (NONMEM®). The selected efficacy endpoint for E-R and D-R models was progression-free survival [PFS], and safety endpoints were rashes of any grade and grade≥3. Exposure parameters included the average daily area under the concentration-time curve (AUC) up to event (AUC_avg), AUC at steady state (AUC_ss), and maximum concentration (C_max,ss) for ensartinib.

Results

A total of 482 subjects deriving from 4 clinical trials (BTP-28311, X396-CLI-101, X396-CLI-301, and BTP-42322) were included in the analysis. The POP-PK properties of ensartinib (n=253) were well described by a one-compartment model with first-order absorption and elimination. The E-R analysis (n=253) indicated positive correlations between AUC_avg and PFS, as well as C_max,ss and selected safety endpoints, respectively (all p<0.05). Besides, 200 mg once daily (QD) ensartinib starting dose yielded a similar PFS (24.3 vs. 26.1 months) compared with 225 mg QD starting dose but milder rashes of any grade (a 2.1% reduction) and grade≥3 (a 5.0% reduction). The D-R analysis (n=482) showed that 200 mg QD starting dose achieved a comparable median PFS (9.7 vs. 11.4 months) compared with 225 mg QD starting dose, but reduced the risk of the rash of any grade by 5.0%.

Conclusions

The POP-PK model of ensartinib was successfully developed and validated for the first time. For the indicated patient populations, a 200 mg QD ensartinib starting dose would provide similar efficacy relative to the 225 mg QD starting dose which was recommended in the instruction of ensartinib, but was associated with a decreased rate of rash.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Betta Pharmaceuticals Co., Ltd.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.