Quantitative Systems Pharmacology Modeling of Loncastuximab Tesirine Combined with Mosunetuzumab and Glofitamab Helps Guide Dosing for Patients with DLBCL
Authors: Li Yuezhe , Wilkins A. Katharina , Knab Timothy , Kirouac Daniel , Boni Joseph 
Published: February 2025

Objectives: The B-lymphocyte surface antigens CD19 and CD20 are clinically validated therapeutic targets to treat B-cell malignancies. Loncastuximab tesirine (loncastuximab tesirine-lpyl [Lonca]) is an antibody–drug conjugate (ADC) that targets CD19. Mosunetuzumab (Mosun) and glofitamab (Glofit) are CD20 × CD3 T cell-dependent bispecific antibodies (TDBs) that redirect T cells to eliminate malignant B cells. By targeting two separate antigens with differing therapeutic modalities, there is potential for combination therapy to improve efficacy as compared to approved monotherapy regimens. Here, we present a quantitative systems pharmacology (QSP) model to predict the efficacy of Lonca and TDB combination therapy in patients with relapsed or refractory diffuse large B-Cell lymphoma (R/R DLBCL). Methods: The model was based on a published and clinically validated physiologically-based pharmacokinetic (PBPK)-QSP model for Lonca in R/R DLBCL [1]. This model was reduced in physiological complexity to be compatible with a published minimal PBPK model of Mosun [2] while maintaining the core functionality of predicting tumor dynamics during Lonca monotherapy. Integrating these 2 models enabled the characterization of both Lonca and TDB induced killing in healthy and malignant B-cells. Results: Improved tumor growth inhibition (TGI) was predicted to result from Lonca and TDB combination therapy compared with any of the agents as monotherapy. While TGI was predicted to plateau by Cycle (C) 2 with Mosun/Glofit monotherapies, the maximum activity of Lonca and TDB combination therapy may not be observed until C4 or later. Additionally, the predicted TGI increased with additional cycles of combination therapy. Conclusions: The results indicate that therapy with Lonca and Mosun/Glofit may promote more TGI by the end of C3 compared with any of these agents alone. Additional cycles of combination therapy, rather than increased doses of Lonca in the TDB combinations, were predicted to increase TGI. Model simulations suggest that Lonca doses could be reduced to improve tolerability for longer periods of time, although clinical testing is required to confirm. The ongoing LOTIS-7 clinical study (NCT04970901) was designed to evaluate the safety and anticancer activity of Lonca in combination with Glofit/Mosun, hence the accuracy of these QSP-model predictions will thus be soon evaluable. The results in this abstract have been previously presented at the AACR Annual Meeting, San Diego Convention Center, April 5-10, 2024, and published in the conference proceedings as abstract #875.Citations: [1] Caimi PF, et al. In relapsed or refractory diffuse large B-cell lymphoma, CD19 expression by immunohistochemistry alone is not a predictor of response to loncastuximab tesirine. EJHaem. 2024; 5(1): 76–83.[2] Hosseini I, et al. Mitigating the risk of cytokine release syndrome in a phase I trial of CD20/CD3 bispecific antibody mosunetuzumab in NHL: impact of translational system modeling. Npj Syst Biol Appl. 2020; 6(1): 1–11.