Optimization of Intravenous Odronextamab Step-up Regimen for Reducing the Risk of High-Grade Cytokine Release Syndrome

Background

Odronextamab is a hinge-stabilized, human CD20×CD3 IgG4-based bispecific antibody that binds CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity, independent of T-cell receptor-mediated recognition. Transient cytokine release is common with T-cell engaging bispecific antibodies, particularly in the early weeks of treatment. This is associated with an increased risk of cytokine release syndrome (CRS), a serious and potentially life-threatening adverse event. As the intensity of cytokine release is positively associated with drug exposures, especially in the first 3 weeks of treatment, administration of lower doses prior to a full treatment dose (i.e. step-up dosing) is a widely used approach to mitigate the risk of CRS.

Intravenous (IV) odronextamab has shown encouraging efficacy in the Phase I ELM-1 study (NCT02290951) in patients with B-cell non-Hodgkin lymphoma (B-NHL). In general, CRS was low grade (Gr), with incidence of Gr ≥3 in 7% of patients across B-NHL histologies despite implementation of a step-up dosing regimen (1 mg/20 mg in Weeks 1-2 with split doses over 2 days) and steroid prophylaxis (Bannerji R, et al. Lancet Haematol. 2022;9:e327-39). The aim of this work was to optimize the step-up regimen to reduce the incidence of Gr ≥3 CRS.

Methods

The following step-up dosing conditions were assessed: 1) The effect of dose on peak odronextamab concentrations in Cycle 1 (C1; Weeks 1-3) including split dosing (equal or unequal split) and addition of more intermediate doses via pharmacokinetics model-based simulations; 2) The projected time profiles of interleukin (IL)-6 (a surrogate cytokine associated with CRS) with a quantitative systems pharmacology (QSP) model under various dosing scenarios (Toroghi, et al. ACoP11 2020. Poster TUE-054); 3) The effect of type and timing of premedication on the occurrence of CRS; and 4) The baseline cytokine levels as a risk factor for Gr ≥3 CRS.

Results

Based on the evaluations of multiple factors as described above, the optimized step-up dosing regimen consists of 0.7 mg (0.2/0.5 mg) split in C1 Day (D) 1 and C1D2; 4 mg (2/2) split at C1D8 and C1D9, and 20 mg (10/10) split at C1D15 and C1D16. Early administration of premedication (12-24 hours prior to first split dose) significantly reduced baseline (pre-treatment) cytokine levels.

Compared with the previously tested regimen, the 0.7/4/20 regimen decreased the total initial dose (Week 1) by 30% (from 1 mg to 0.7 mg), with a more marked reduction of 60% on C1D1 (from 0.5 mg to 0.2 mg). This resulted in a mean observed peak drug concentration reduction of ~50% on C1D1 and a median peak IL-6 concentration post-treatment of 21.1 pg/mL (range 0.6-1163), corresponding to a 17% reduction compared with that from 0.5 mg on C1D1 (median 25.5 pg/mL [range 0.8-3560]).

The dose reduction on C1D1 and the addition of the 4 mg intermediate dose at C1D8 and C1D9 reduced the intensity of cytokine release compared with the previously tested 1 mg (0.5/0.5)/20 mg (10/10) doses, according to the QSP simulation. This new regimen has been tested in clinical studies in patients with follicular lymphoma and diffuse large B-cell lymphoma. As of April 20, 2022, there have been no Gr ≥3 CRS in the first 87 patients treated with the optimized regimen.

Importantly, although the optimized odronextamab IV step-up dosing regimen showed a lower concentration of odronextamab compared with the original regimen during Cycle 1, the concentrations were similar after the first full dose was administered, with similar trough concentrations after Week 4. This indicates that the same therapeutic levels are achieved with both regimens, which is beneficial for the treatment of disease.

Conclusion

This optimized odronextamab dosing regimen was associated with lower risk of CRS and lower levels of baseline cytokine levels compared with the original regimen. The drug exposure was lower in the first cycle when the risk of CRS is greater, but it was comparable to that of the original regimen after the full dose of treatment was received, ensuring that odronextamab dose levels required for efficacy are maintained.

Zhu:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Brouwer-Visser:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Ambati:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Mohamed:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Jankovic:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Wang:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Yan:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Cai:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Leite De Oliveira:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Ufkin:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Davis:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Chaudhry:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Khaksar Toroghi:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company.

Odronextamab for the treatment of patients with B-cell non-Hodgkin lymphoma.