ABCL-366 Quantitative Systems Pharmacology Model Predicts Combination Activity of CD19-Targeted Loncastuximab Tesirine Co-Dosed With a CD20/CD3 T-Cell Bispecific (Epcoritamab) in Diffuse Large B-Cell Lymphoma

• Published in: Clinical lymphoma, myeloma and leukemia myeloma and leukemia, 2024-09, Vol.24, p.S475-S475
• Main Authors: Li, Yuezhe, Wilkins, A. Katharina, Davis, Jimena, Knab, Timothy, Keir, Chris, Boni, Joseph P.
• Format: Article
• Language: English
• Subjects: ABCL; epcoritamab; loncastuximab tesirine; non-Hodgkin lymphoma; quantitative systems pharmacology modeling
• ISSN: 2152-2650
• DOI: 10.1016/S2152-2650(24)01520-9

Loncastuximab tesirine (loncastuximab tesirine-lpyl [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). Epco and Lonca target different B-cell antigens, and combining both could have additive or synergistic efficacy. Previously, a novel quantitative systems pharmacology (QSP) model for Lonca was developed and validated with clinical data. A QSP model for Lonca + Epco in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) is described to predict combined antitumor activity. The previous Lonca model was simplified while maintaining core functionality and combined with a QSP model for bsAbs to predict tumor dynamics after Lonca and/or Epco treatment. Assumptions included the following: Lonca/Epco induce healthy and malignant B-cell killing, tumor comprises T cells and malignant B cells, tumor volume is based on malignant B-cell count, T cells can enter/leave tumor, and CD19-/low CD20+ B cells account for tumor heterogeneity from cells insensitive to Lonca. Tumor growth inhibition (TGI) was predicted to plateau by cycle (C)2 with Epco monotherapy. By end of C3, predicted median normalized tumor volume reduction with codosing was approximately one log order greater than Epco alone. Maximum activity of Lonca and Epco was not observed until C4+, as depth of TGI increased with additional treatment cycles. Furthermore, a 50% decrease at baseline in T cells significantly reduced antitumor effect with Epco alone but made no difference with Lonca in combination. By end of C3, Lonca + Epco was predicted to promote substantially more TGI than Epco or Lonca alone. While increased doses of Lonca had limited additional therapeutic benefit, combination treatment beyond C3 was predicted to increase depth of tumor regression. Response from Lonca and Epco codosing was predicted to be less affected by suppressed T-cell counts at baseline compared with Epco alone, which may enhance responsiveness when T-cell level is moderate. © 2024 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted for publication at the 2024 ASCO Annual Meeting. All rights reserved.