Abstract 2130: Optimization of tarlatamab step-up dosing regimen to mitigate cytokine release syndrome using quantitative systems pharmacology modeling

Abstract Tarlatamab is a DLL3/CD3 bispecific T-cell engager (TCE) recently approved by the FDA for the treatment of extensive-stage small cell lung cancer (ES-SCLC). The dosing follows a step-up regimen for the first cycle, with 1 mg given on day 1, and 10 mg given on days 8 and 15. A similar step-up dosing regimen, but with 100 mg instead of 10 mg, was also tested in a pivotal phase 2 trial (Ahn et al. N Engl J Med. 2023 Nov 30;389(22):2063-2075). The alternative step-up dose or step-up regimen were not investigated in the study. The aim of our work was to explore the alternative step-up regimens of tarlatamab, predicting trimer (complex of TCE with target receptors) kinetics in the tumor using quantitative systems pharmacology (QSP) modeling. The QSP model integrated pharmacokinetics of tarlatamab, its distribution into the tumor of patients with ES-SCLC, binding with CD3 expressed by T-cells and DLL3 expressed by cancer cells, formation of trimer in the immunological synapse between T-cell and cancer cell, turnover of free and bound receptors, trimer internalization. Predicted peak trimer levels in the tumor are associated with cytokine release syndrome (CRS) incidence following tarlatamab administration. Higher peak levels of trimer are predicted for the doses and regimens causing more frequent CRS events. The model showed that 1 mg is the optimal step-up dose for the regimens tested in clinical trials since lower doses led to a higher peak trimer level after second dose (10 mg given on day 8). However, split dosing of the 1st or 2nd doses and a longer step-up schedule decreased the peak trimer levels following tarlatamab administration. Splitting the first dose in the approved regimen resulted in a reduction of peak trimer by 30-40%, thus mitigating CRS incidence. Administration of the 0.5 mg on day 1 and 0.5 mg on day 4 also caused a minor decrease of peak trimer level after administration of 10 mg on day 8. A substantial reduction of the maximal level of the trimer after the second dose was predicted for the step-up regimen with 100 mg if the second dose given on day 8 is 3 mg instead of 100 mg. This dose optimization might lower the probability of CRS grade 3 events observed in patients treated with 100 mg. Split-dose regimens and regimens with more than one step-up dose allow for minimizing CRS incidence without compromising the efficacy of TCEs. QSP modeling is a useful tool to investigate various doses and regimens of bispecific and multispecific antibodies. Citation Format: Oleg Demin Jr, Galina Kolesova, Dmitry Shchelokov. Optimization of tarlatamab step-up dosing regimen to mitigate cytokine release syndrome using quantitative systems pharmacology modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2130.