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

Abstract

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 2018). qCP analyses of TCZ PK and s-IL6R data from 67 pts who received TCZ for CRS management following treatment with Mosun or Glofit indicated that this TCZ regimen may exceed the safety threshold, in part because maximum TCZ conc is one-third lower in pts with CAR T-cell-induced CRS vs bispecific antibody-induced CRS. In addition, typical bispecific antibody regimens involve multiple doses compared with a single CAR T-cell infusion, with the potential for multiple CRS events requiring TCZ treatment; therefore, TCZ accumulation must be considered. qCP simulations predicted that for 1 x 8 mg/kg dose, median duration of >90% s-IL6R saturation was 28 (range: 14-28) days ( Table). Furthermore, simulations indicated that ≤2 consecutive TCZ doses q8h per CRS event and a maximum of 3 TCZ doses within a 6-week time period maintain the TCZ conc below the FDA safety threshold, while ensuring sustained s-IL6R occupancy ( Table). Conclusions: qCP results and clinical experience in Mosun and Glofit studies support a TCZ dosing regimen of ≤2 IV doses of 8 mg/kg per CRS event administered q8h, not exceeding a total of 3 doses within a 6-week period. Further improvement in CRS management and symptom resolution with additional TCZ doses is unlikely given the predicted duration of s-IL6R occupancy and observed rapid decline in systemic inflammatory markers post dosing. This proposed TCZ dosing regimen reflects TCZ usage patterns in clinical trials evaluating Mosun and Glofit, and is included in their Summaries of Product Characteristics. In patients with R/R B-NHL receiving bispecific antibody treatment, TCZ is generally suitable for management of acute CRS, and balances risk-benefit for potential scenarios involving multiple TCZ administrations for pts with CRS recurrence. This recommendation considers TCZ safety factors, the unique PK properties of TCZ in this setting and the expected duration of activity based on pharmacological modeling of target binding (s-IL6R occupancy).