Quantitative systems pharmacology (QSP) model to predict combination activity of CD19-targeted antibody drug conjugate (loncastuximab tesirine) co-dosed with a CD20/CD3 T-cell bispecific (epcoritamab) in patients with diffuse large B-cell lymphoma (DLBCL).

Abstract

e19059 Background: Loncastuximab tesirine-lpy (Lonca) is an antibody-drug conjugate comprising an anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer cytotoxin. Epcoritamab-bysp (Epco) is a CD20×CD3 T cell-engaging bispecific antibody (bsAb) that redirects T-cells to eliminate malignant B-cells. Epco and Lonca target different B-cell surface antigens and combining both is expected to have additive or synergistic efficacy. Previously, a novel QSP model for Lonca was developed (Utsey K et al. Clin Pharmacol Drug Dev. 2023;12:123-125) and validated with clinical data from patients with R/R DLBCL (Caimi P et al. Blood. 2022;140:9548-9550). A combination QSP model for Lonca with Epco in R/R DLBCL was described to predict potential anti-tumor synergies in proposed clinical trials. Methods: The model reduced previous Lonca model complexity while maintaining core functionality and was combined with a published QSP model for T-cell bsAbs (Hosseini I et al. Npj Syst Bio Appl. 2020;6(1):1-11) to predict tumor dynamics after Lonca and/or Epco treatment. Assumptions included: 1) Lonca or Epco induce healthy and malignant B-cell killing; 2) tumor comprises malignant B- & T-cells; 3) tumor volume is based on malignant B-cell count; 4) T-cells can enter or leave tumor as with other tissues; 5) CD19-/low CD20+ B-cells account for tumor heterogeneity from cells insensitive to Lonca treatment. Results: Tumor growth inhibition (TGI) was predicted to plateau by Cycle (C) 2 with Epco monotherapy. By end of C3, however, predicted median normalized tumor volume reduction with co-dosing Lonca and Epco was approximately 1 log order greater than Epco alone. Maximum activity of Lonca and Epco therapy was not observed until C4 or later as depth of tumor regression increased with additional treatment cycles. Since patients with DLBCL may present with low T-cell counts (Hutchings et al. Lancet. 2021) the effect of T-cell count at baseline was evaluated. A 50% decrease at baseline from 2000-1000 T-cells/µL significantly reduced antitumor effect with Epco alone but made no difference with Lonca in combination. Conclusions: These results resemble predictions for Lonca in combination with other bsAbs (Lonca plus mosunetuzumab or glofitamab; abstract submitted to AACR 2024). By end of C3, Lonca plus Epco was predicted to promote substantially more TGI than Epco or Lonca alone. While increased doses of Lonca from 90-150 µg/kg in combination had limited additional therapeutic benefit, combination treatment beyond C3 was predicted to increase depth of tumor regression. Response from Lonca and Epco co-dosing was predicted to be less affected by suppressed T-cell counts at baseline compared to Epco alone; a feature that may enhance responsiveness when T-cell level is moderate.