PI-095 - BLINATUMOMAB TRIMER FORMATION - INSIGHTS FROM A MECHANISTIC PKPD MODEL ON THE IMPLICATIONS FOR SWITCHING FROM INFUSION TO SUBCUTANEOUS DOSING REGIMEN IN ACUTE LYMPHOBLASTIC LEUKEMIA AND NON-HODGKIN’S LYMPHOMA.

G. Kapitanov, S. Head, V. Chang, D. Flowers, J. Apgar, J. Grant; Applied BioMath, Concord, MA, USA.

Background: Blinatumomab is a bispecific T-cell engager (BiTE) that binds to CD3 on T cells and CD19 on B cells. It has been approved for use in Acute lymphoblastic leukemia (ALL) with a regimen that requires continuous infusion (cIV) for four weeks per treatment cycle [1]. It is currently in clinical trials for Non-Hodgkin’s Lymphoma (NHL) with cIV administration [2]. Recently, there have been studies investigating dose-response after subcutaneous (SC) dosing in ALL and in NHL, and whether this more convenient method of delivery would have a similar efficacy/safety profile as continuous infusion. It has been hypothesized that the pharmacological effect of BiTEs is due to trimolecular complexes (trimers) formed between T cells and malignant cells. In this work, a model-based investigation compares the trimer formation between the two delivery methods.

Methods: We constructed mechanistic PKPD models of ALL and NHL that describe blinatumomab PK in circulation, at the site of action (the bone marrow for ALL and tumor for NHL) and periphery, engagement with CD3 on T cells and CD19 on normal and malignant B cells, and the amount of trimers the drug forms at different dosing administrations and regimens.

Results: The explored SC doses in ALL and NHL achieve similar trimer numbers as the cIV doses in those indications. We further simulated various potential subcutaneous dosing regimens, and identified conditions where trimer formation dynamics are similar between constant infusion and subcutaneous dosing when accounting for cell death resulting from the trimer formation. Potential SC dose regimens to take into later studies are identified based on the trimer metric.

Conclusion: Based on the model, subcutaneous dosing is a viable and convenient strategy for blinatumomab and is projected to result in similar trimer numbers as constant infusion.

[1] BLINCYTO (blinatumomab) [package insert], Thousand Oaks, CA, Amgen Inc., 2022
[2] Martinez-Sanchez et al. Safety and Efficacy of Subcutaneous (SC) Blinatumomab for the Treatment of Adults with Relapsed or Refractory B Cell Precursor Acute Lymphoblastic Leukemia (R/R B-ALL) [poster], American Society Of Hematology Annual Meeting, 2021