A Novel Step‐Up Dosage Regimen for Enhancing the Benefit‐to‐Risk Ratio of Mosunetuzumab in Relapsed or Refractory Follicular Lymphoma

Mosunetuzumab, a T‐cell engaging bispecific antibody targeting CD20xCD3, is approved for treating relapsed/refractory follicular lymphoma. This research supports the approved intravenous clinical dose regimen, summarizing the exposure–response relationships for clinical safety and efficacy. A population pharmacokinetic model and E max logistic regression exposure–response models for safety and efficacy were developed using data from 439 patients with relapsed/refractory non‐Hodgkin lymphoma and 159 patients with relapsed/refractory follicular lymphoma, respectively, from a Phase I/II study (NCT02500407). Data from 0.2 to 60 mg across fixed dosing (Cohort A) and Cycle 1 step‐up dosing (Cohort B) were used. Exposure–response models, using two‐cycle area‐under‐the‐concentration curve (AUC 0–42 ) as the primary exposure endpoint, accurately depicted the complete response and objective response rate data across a 600‐fold AUC 0–42 range. The approved clinical dose regimen of 1/2/60/30 mg achieved near‐maximal efficacy, with model‐estimated CR and ORR (90% confidence interval) of 63.1% (49.7–75.0) and 79.1% (69.1–87.7), respectively. The exposure–response analysis for Grade ≥ 2 cytokine release syndrome identified receptor occupancy (%) within the first two cycles as a driver, with CRS dissipating beyond the first dosing cycle. No exposure‐dependent increases were observed for other serious adverse events, including neutropenia and infections. The approved intravenous step‐up dose regimen (i.e., step doses of 1 and 2 mg on Day 1 and 8, respectively) mitigated severe CRS risk, allowing safe administration of loading (60 mg) and target doses (30 mg every 3 weeks) to achieve a favorable benefit–risk profile.