Cytokine Release Syndrome: Trends with T Cell Engaging Bispecifics from a Systematic Review of Licensing Applications

Effective prevention, mitigation, and management of cytokine release syndrome (CRS) is crucial in T cell engaging bispecific (TCE) development. We systematically reviewed the biologics licensing applications (BLAs) of 7 approved hematologic TCEs, gathering pan-molecule evidence on CRS clinical pharmacology. Mosunetuzumab and elranatamab had the lowest CRS risk among TCEs for non-hodgkin's lymphoma (NHL) (range 39-70%) and multiple myeloma (MM) (range 58-79%), respectively. Grade 2+ CRS was low for all approved molecules (ranged from 15% to 22%). All TCEs employed a 2 step priming approach, except blinatumomab (1 step; continuous infusion) and talquetamab bi-weekly (3 step), and were successful at mitigating CRS beyond the first full dose. Subcutaneous (SC) administration for CRS mitigation remains an inconclusive strategy across molecules; no TCEs are approved for intravenous and SC administration. Pharmacological characterization of CRS included cytokine dynamics and drug exposure-response (E-R) analysis for TCEs approved after 2021. IL-6 time profiles were reported for all TCEs along with IL-10 and IFN-y in 4/6 cases. Peak levels for one or more cytokines trended with dose-period CRS rates, but not consistently for all cytokines and molecules, further suggesting that the cytokine to CRS relationship is complex. Positive trends in CRS E-R were reported for 4/6 TCEs when the drug's maximum concentration (Cmax) or receptor occupancy were used as the exposure driver. E-R analyses were typically performed for each dose period through the first target dose. Covariates associated with CRS included baseline factors (disease status, treatment history, target level, effector cell status, age) and on-treatment factors (tocilizumab use, prior Cmax). Hospitalization is required for all TCEs except mosunetuzumab. Thus, further characterizing CRS and establishing a link between drug levels, biomarkers, and clinical events will not only aid TCE development but also benefit patients by reducing the need for intensive clinical interventions and hospitalization. Quantitative clinical pharmacology methods including mechanism- and empirical-based approaches will continue to be instrumental in TCE development, especially as regimens become more complex with combination and pretreatment integration.

Radtke:Genentech, Roche: Current Employment, Current equity holder in publicly-traded company. Bender:Genentech, Roche: Current Employment, Current equity holder in publicly-traded company. Li:Genentech, Roche: Current Employment, Current equity holder in publicly-traded company. Turner:Genentech, Roche: Current Employment, Current equity holder in publicly-traded company. Roy:Genentech, Roche: Current Employment, Current equity holder in publicly-traded company. Belousov:Roche: Current Employment, Current equity holder in publicly-traded company. Li:Genentech, Roche: Current Employment, Current equity holder in publicly-traded company.