(M-092) QSP modeling to inform key clinical dosing regimen decisions for an engineered IL15 cytokine Efbalropendekin alfa in patients with solid tumors
Dan Lu, Ph.D.: No financial relationships to disclose
Victor Poon, MS: No financial relationships to disclose
Objectives: Efbalropendekin alfa (EBA), is an IL-15/IL-15Rα-Fc fusion protein engineered to target and preferentially expand CD8+ T cells and NK cells but not regulatory T cells, and reduce acute toxicity. A Phase I study tested EBA as a single agent or in combination with atezolizumab (ATZ)1 in patients with solid tumors1. Initial dose escalation explored an every-two-weeks (Q2W) dosing regimen; emerging tolerability data raised concerns of spleen enlargement, leading us to consider further dose and frequency optimization. Preclinical studies demonstrated PD-enhanced target-mediated drug disposition (TMDD) properties of EBA2, which were described and explored in a QSP model 2 including the components of systemic and peripheral lymphocyte expansion. Here we adapt the QSP model to evaluate the impact of dose and regimen on key clinical PD and safety metrics to support dosing regimen (dose level and frequency) optimization.
Methods: A QSP model, previously developed using preclinical data2, was recalibrated to simultaneously describe the available clinical PK, PD (i.e., NK cell, CD8+ T-cell and CD4+ T-cell peripheral blood dynamics), and patient spleen volume dynamics, with the majority of data from Q2W regimen. Simulations were then performed to compare predicted NK and CD8+ T-cell dynamics across multiple dosing regimens of interest for clinical development, including Q2W dosing at 0.06, 0.09, and 0.12 mg/kg and Q4W dosing at 0.09, 0.12, and 0.18 mg/kg.
Results: The calibrated QSP model provided a good fit for the observed PK, PD and spleen volume dynamics across multiple EBA dosing regimens. Model simulation suggested that the rank order of the fold of NK cell expansion and spleen volume increase are overall consistent with the dose intensity per week from Q2W or Q4W regimens: 0.09 Q4W < 0.12 Q4W ~ 0.06 Q2W < 0.18 Q4W ~ 0.09 Q2W < 0.12 Q2W. For the two regimens of most interest (0.12 mg/kg Q4W & 0.09 mg/kg Q2W), the model simulation suggested: Day 35 NK cells were ~50 and 60 fold of baseline respectively, Day 35 CD8+ T cells were ~2.0 and 1.8 fold of baseline, and Day 42 (Week 6) spleen volumes were ~100% and 130% increase above baseline. This was qualitatively consistent with the clinically observed mean [min-max, N] values of 43.8 [1.79-115, N=11] and 55.3 [10.9-90.9, N=3] fold for NK cells; 1.47 [0.529-3.12, N=11] and 1.56 [1.04-1.96, N=3] fold for CD8+ T cells; 106% [39-252%, N=18] and 139% [107-173%, N=5] increase above baseline for spleen volumes. The model simulation also suggested a less rapid spleen enlargement for the 0.12 mg/kg Q4W regimen, compared to 0.09 mg/kg Q2W, qualitatively aligned with observed data.
Conclusions: The QSP model identified dose intensity per week as the key driver for the speed and extent of NK cell expansion and spleen volume increase. Model simulation suggested a slower NK cell expansion trend and a reduced risk of rapid spleen enlargement while preserving similar peripheral CD8+ T cell expansion for the 0.12 mg/kg Q4W compared to the 0.09 mg/kg Q2W regimen. These results were considered in totality with the preclinical and clinical data1 to support the implementation of dose escalation with the Q4W regimen (instead of Q2W) to enable higher dose levels while keeping a similar or lower dose intensity compared to Q2W 1.
Citations: [1] Tran B. et. al., Phase Ia/Ib dose-escalation study of efbalropendekin alfa (XmAb24306) as single-agent and with atezolizumab in solid tumors. AACR 2025 [2] Lu D. et. al., Complex PK-PD of an engineered IL-15/IL-15Rα-Fc fusion protein in cynomolgus monkeys: QSP modeling of lymphocyte dynamics. Eur J Pharm Sci. 2023
