PI-125 - QUANTITATIVE SYSTEMS PHARMACOLOGY MODELING OF LONCASTUXIMAB TESIRINE-LPYL COMBINED WITH T CELL-DEPENDENT BISPECIFIC ANTIBODIES BRIDGES KNOWLEDGE AND DOSE REGIMEN STRATEGY FOR PATIENTS WITH DIFFUSE LARGE B CELL LYMPHOMA

D. Kirouac¹, Y. Li², A. Wilkins², J. Davis², T. Knab³, M. Toukam⁴, J. Boni⁴; ¹Metrum Research Group, Coneticut, USA, ²Metrum Research Group, CT, USA, ³Meterum Research Group, CT, USA, ⁴ADC Therapeutics America Inc, NJ, USA.

Background: Antibody drug conjugates (ADCs) and T cell–dependent bispecific antibodies (TDBs) have proven single-agent efficacy in relapsed/refractory (R/R) lymphomas. Coadministering therapeutics with distinct mechanisms of action is a potential means of enhancing efficacy while minimizing dose-limiting toxicities. However, it is not feasible to empirically test every potential drug combination and coadministration regimen in clinical trials. Predictive, quantitative systems pharmacology (QSP) models could thus prove valuable as a means of simulating alternate treatment regimens to guide optimal clinical trial design.

Methods: An integrated systems pharmacology model of a CD19-targeted ADC (loncastuximab tesirine-lpyl) and CD3/CD20-targeted TDBs (mosunetuzumab, glofitamab, and epcoritamab) was developed to predict combination regimen efficacy in R/R diffuse large B cell lymphoma (DLBCL). Clinically validated models of loncastuximab tesirine and mosunetuzumab were taken from the literature, simplified, integrated while maintaining core functionality, and extended to additional TDBs. A virtual population was constructed by randomizing five key model parameters and prevalence weighting against reported monotherapy response data for the individual drugs. Combination effects on tumor volume dynamics were then simulated under multiple dosing regimens and patient population scenarios.

Results: Simulations predicted that combination antitumor effects between loncastuximab tesirine and TDBs appeared by the fourth treatment cycle, outperforming either TDB or loncastuximab tesirine monotherapy. Antitumor effects increased with subsequent treatment cycles in an additive manner, were insensitive to reductions in loncastuximab tesirine dose, and were maintained in lymphopenic patients.

Conclusion: The virtual population-based lymphoma QSP model enabled systematic exploration of alternate drug combinations, dosing schemes, clinical covariates and resultant effects on anti-tumor activity in silico. The results of the LOTIS-7 study (NCT04970901), a platform study evaluating loncastuximab tesirine in combination with glofitamab and mosunetuzumab, will soon be available to assess the accuracy of the model predictions.