New Tocilizumab (TCZ) Dosing Guidance for T-Cell Engaging Bispecific Antibody-Related Cytokine Release Syndrome (CRS) in Patients (pts) with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (B-NHL): Insights from Pooled Clinical Trial Safety Experience and Quantitative Clinical Pharmacology (qCP) Analyses

Background: Mosunetuzumab (Mosun), approved for treatment of pts with R/R follicular lymphoma (FL) and ≥2 prior therapies, and glofitamab (Glofit), approved for treatment of pts with R/R diffuse large B-cell lymphoma, or large B-cell lymphoma arising from FL, and ≥2 prior therapies, are CD20xCD3 T-cell engaging bispecific antibodies that redirect T cells to eliminate B cells. CRS is a common on-target adverse event observed with bispecific antibodies and associated with exposure. TCZ, a humanized anti-interleukin-6 (IL-6) receptor, is often used for CRS management. TCZ dosing recommendations derived from CAR T-cell studies (Le et al. Oncologist 2018) may not be optimal for bispecific antibody-treated pts. Using TCZ clinical usage patterns in Mosun- or Glofit-treated pts with R/R B-NHL, qCP, and cytokine analyses, we explored a new TCZ dosing regimen for CRS management (for pts >30 kg body weight). Methods: Pooled safety data from seven Phase I/II studies evaluating Mosun or Glofit in pts with R/R B-NHL were analyzed. CRS was graded using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Modeling was used to predict TCZ concentrations (conc) and soluble IL-6 receptor (s-IL6R) occupancy over time, following administration of different TCZ dosing regimens in a subset of pts. Downstream cytokine pharmacodynamic responses (IL-6 and C-reactive protein [CRP]) were evaluated graphically post-TCZ dosing. Results: Data from 733 Mosun- and 772 Glofit-treated pts across different Mosun/Glofit dose levels were analyzed; of these, 232 (31.7%) and 427 (55.3%) pts, respectively, had ≥1 CRS event, and 36/232 (15.5%) and 140/427 (32.8%) pts received TCZ for CRS management. CRS events were mainly Grade 1/2 and occurred during the first treatment cycle. Most pts who received TCZ for CRS received ≤2 doses of TCZ overall (Mosun: 94.4%; Glofit: 84.2%) ( Table), and 1 dose of TCZ for the management of a single CRS event (Mosun: 91.7%; Glofit: 84.9%). CRS resolution was achieved within 3 days of TCZ administration in 75.0% and 66.9% of Mosun- and Glofit-treated pts, respectively. By then, a reduction in IL-6 and CRP levels was also observed. In a prior pharmacokinetic (PK) analysis of TCZ in pts with CAR T-cell-associated CRS, predicted TCZ conc after administration of 4 intravenous (IV) TCZ doses of 8 mg/kg every 8 hours (q8h) was generally below 649 μg/mL, the observed maximum conc in healthy volunteers and “safety threshold” used by the FDA (Le et al. Oncologist 20