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

• Published in: Clinical pharmacology and therapeutics
• Main Authors: Li, Chi-Chung, Bender, Brendan, Wilkins, Justin, Li, Feifei, Turner, David C, Wang, Bei, Deng, Rong, Vadhavkar, Shweta, Li, Zao, Kwan, Antonia, Huang, Huang, Peng, Kun, Penuel, Elicia, Huw, Ling-Yuh, Chanu, Pascal, Li, Chunze, Yin, Shen, Wei, Michael C
• Format: Journal Article
• Language: English
• Published: United States 27.09.2024
• ISSN: 1532-6535
• DOI: 10.1002/cpt.3445

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 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 ) as the primary exposure endpoint, accurately depicted the complete response and objective response rate data across a 600-fold AUC 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.