057: Quantitative Systems Pharmacology Modeling of Loncastuximab Tesirine Combined With Mosunetuzumab & Glofitamab Guides Dosing in B-cell Lymphoma

Statement of Purpose, Innovation or Hypothesis: CD19 and CD20, B-lymphocyte surface antigens, are clinically validated therapeutic targets for the treatment of B-cell malignancies. Loncastuximab tesirine (loncastuximab tesirine-lpyl [Lonca]) is an antibody–drug conjugate comprising an anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer cytotoxin. Mosunetuzumab (Mosun) and glofitamab (Glofit) are CD20 × CD3 T-cell–engaging bispecific antibodies (bsAbs) that redirect T cells to eliminate malignant B cells. These agents target a different B-cell surface antigen than Lonca; hence, combining Lonca with either one of these bsAbs is expected to have additive or even synergistic efficacy. Previously, a novel physiologically-based pharmacokinetic (PBPK)–quantitative systems pharmacology (QSP) model was developed (Utsey K, et al. Clin Pharmacol Drug Dev. 2023;12:123-125) and validated with Lonca monotherapy clinical observations in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) (Caimi P, et al. Blood. 2022;140:9548-9550). Modeling results of Lonca in combination with Mosun or Glofit in R/R DLBCL are described herein.

Description of Methods & Materials: The model was based on the previously validated and published Lonca PBPK-QSP model. This model was reduced in physiological complexity to be compatible with a published minimal PBPK model of Mosun (Hosseini I, et al. NPJ Syst Biol Appl. 2020;6:28) while maintaining the core functionality of predicting tumor dynamics during Lonca monotherapy. The following assumptions were made: (1) Lonca or Mosun/Glofit induce healthy and malignant B-cell killing; (2) the tumor comprises malignant B cells and T cells; (3) tumor volume is calculated using malignant B-cell number; and (4) T cells can enter or leave the tumor as they enter or leave other tissues.

Data & Results: Improved tumor growth inhibition (TGI) should result from Lonca + bsAb combination therapy compared with any of the agents as monotherapy. While TGI was predicted to plateau by cycle (C) 2 with Mosun and Glofit monotherapies, the maximum activity of Lonca + bsAb combination therapies may not be observed until C4 or later. Additionally, the predicted TGI increased with additional treatment cycles.

Interpretation, Conclusion or Significance: Results indicate that treatment by the end of C3 for Lonca + Mosun and by the end of C4 for Lonca + Glofit would promote substantially more TGI compared with any of these agents alone. Increased doses of Lonca in combinations were predicted to have limited additional therapeutic benefit; however, additional cycles of combination treatment were predicted to increase TGI. This model suggests that Lonca doses could be reduced to allow for improved tolerability for longer periods of time, up to the point of maximal benefit, although clinical testing is needed to explore these results. The ongoing LOTIS-7 clinical trial (NCT04970901) evaluates the safety and anticancer activity of Lonca in combination with both Glofit and Mosun.

Disclosures: Li: employee of Metrum Research Group. Wilkins: employee of Metrum Research Group. Knab: employee of Metrum Research Group. Boni: employee and a current equity holder at ADC Therapeutics America Inc, a publicly traded company.

Funding: ADC Therapeutics SA and Swedish Orphan Biovitrum AB medical writing: Citrus Health Group.

Encore Presentation: American Association of Cancer Research, April 15-20, 2024