PI-028 - CLINICAL PHARMACOKINETICS AND BIOMARKER ANALYSES OF RC88, A NEW MESOTHELIN-TARGETING ANTIBODY DRUG CONJUGATE, IN PATIENTS WITH ADVANCED SOLID TUMORS

Y. Guo¹, W. Yu¹, M. Li¹; ¹RemeGen Co., Ltd., Beijing, China.

Background: RC88 is an antibody-drug conjugate, consisting of a mesothelin (MSLN) targeting antibody conjugated to monomethyl auristatin E (MMAE). The target mesothelin (MSLN) is shed into the plasma as soluble MSLN-related protein (SMRP) and is associated with the tumor marker CA125, particularly in ovarian cancer. To assess the pharmacokinetics (PK) and evaluate the impact of biomarkers on PK and clinical responses, the preliminary results from RC88 in an ongoing phase I/IIa clinical trial were evaluated.

Methods: NCT04175847 is a multicenter, open-label, multi-cohort study that includes dose escalation and multi-cohort extension. Patients received RC88 monotherapy. IV infusion were given at 0.1 to 3.0 mg/kg every 3 weeks (Q3W) for the dose escalation stage, and at 2.0 to 2.5 mg/kg (Q3W) for the dose expansion stage. Intensive PK sampling was conducted on Cycle 1 and Cycle 3. PK characterization was performed for the RC88 conjugated antibody (ADC), total antibody (TAB), and free MMAE using non-compartmental analysis (NCA). Blood levels of CA125 and SMRP were measured and visually compared with PK and clinical responses.

Results: A total of 170 patients were enrolled at present and received treatment with RC88 Q3W. After the first dose, exposures of ADC, TAB, and free MMAE increased proportionally across doses of 0.5 to 2.5 mg/kg. The average half-life ranged from 1.03 to 1.77 days for ADC and 2.16 to 2.38 days for TAB. The free MMAE reached its peak concentration approximately 3 days after infusion, and its half-life ranged from 2.86 to 3.31 days. No accumulation of these three analytes was observed after multiple doses. SMRP data were available from 164 patients with solid tumor and CA125 data were available for 59 patients with ovarian cancer. SMRP and CA125 showed comparable baseline levels in responders and non-responders. There were no differences in exposure and PK parameters among patients with different baseline SMRP or CA125 levels. In ovarian cancer, a greater decrease in post-dose CA125 levels from baseline was associated with better clinical response.

Conclusion: RC88 demonstrates a linear pharmacokinetic (PK) profile within the 0.5-2.5 mg/kg dose range. Baseline levels of CA125 and SMRP do not influence PK parameters, whereas changes in post-dose CA125 levels might be correlated with clinical outcomes.