Scientist Pumas-AI, inc. Keller, Texas, United States
Background: Botensilimab (Bot), a novel Fc-enhanced IgG1 anti-CTLA-4 antibody designed to optimize FcγR co-engagement and enhance anti-tumor immunity against 'cold' tumors, is being developed in combination with balstilimab (Bal), an IgG4 anti-PD-1 antibody. This combination has shown clinical activity in advanced colorectal cancer (CRC) and other refractory solid tumors. To support fixed dosing in CRC, we developed a popPK model characterizing Bot concentrations alone or with Bal in advanced solid tumors. Methods: The popPK analysis included 4134 Bot concentration values from 718 patients with advanced solid tumors who received Bot intravenously as monotherapy or in combination with Bal across three Phase I and II clinical studies. Bot doses ranged from weight-based doses of 0.1 to 2 mg/kg every 3 weeks (Q3W) or every 6 weeks (Q6W), 3 mg/kg Q3W, and fixed doses of 50 mg Q3W, 75 mg Q6W, 150 mg Q3W and 150 mg Q6W. Model development involved 3 steps: (i) a base model to identify the structural and statistical models, (ii) a full model incorporating parameter-covariate relationships, and (iii) a final model refined by backward elimination. Simulations were conducted to assess the conversion from weight-based to fixed dosing. Results: A linear 2-compartment model with IV infusion and stationary clearance (CL) best described the Bot PK data. The geometric mean (GM) terminal half-life was 14 days. The final popPK model included interindividual variability (IIV) terms on CL, central volume of distribution (Vc), and intercompartmental clearance (Q); along with body weight effects on CL and Vc. In addition, albumin, age, tumor type, ECOG status, and combination therapy all were statistically significant in describing the IIV on Bot CL, but not clinically relevant. Model-based simulations of steady-state Cavg and Ctrough of 75 mg Q6W showed all less than 1.2 % higher GM exposure compared to 1 mg/kg Q6W, that remains within the equivalence range of [0.80 - 1.25]. Similar trends were observed upon comparison of 150 mg and 2 mg/kg Q6W. Conclusion: Bot PK is well characterized. Minimal effects of intrinsic and extrinsic factors on exposure, including presence of ADA+, were observed, indicating no need for dose adjustments. Simulation results showed similarity in Bot exposure between weight–based and fixed dosing thus supporting conversion to the fixed doses of 75 and 150 mg.
