Continuous or Fixed-Duration Treatment for CD3xCD20 Bispecifics: A Modeling and Simulation Study Using Epcoritamab Monotherapy
Authors: Liao Xiaozhi , Li Tommy , Xu Steven , Mohamed Mohamed-Eslam F , Sinnollareddy Mahipal , Gupta Manish , Wielgos-Bonvallet Monica , Steele Andrew J. , Sacchi Mariana , Cao Yanguang 
Published: December 2024

Introduction
Epcoritamab is a CD3xCD20 bispecific antibody approved for adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma and R/R follicular lymphoma. The recommended regimen is to administer epcoritamab in 28-day cycles and continue treatment until disease progression or unacceptable toxicity. Both continuous treatment and fixed-duration regimens are proposed for other CD3xCD20 bispecific antibodies. While the fixed-duration regimen is hypothesized to reduce toxicity due to long-term exposure, the continuous regimen might extend the response duration and improve survival outcomes. It remains unclear which regimen provides better clinical benefit to patients. This study employed epcoritamab monotherapy data and modeling/simulation methods to compare the outcomes of the two epcoritamab regimens in treating patients with aggressive non-Hodgkin lymphoma (aNHL) and to identify patients that benefit from the continuous regimen.
Methods
An integrated model was developed to link epcoritamab pharmacokinetics (PK), tumor growth dynamics, and Deauville score by fluorodeoxyglucose positron emission tomography (FDG-PET). This model was developed and validated using aNHL patients' data from a phase 1/2 study (NCT03625037). Model parameters were estimated using nonlinear mixed-effects (NLME) models in NONMEM. Complete response (CR) was defined as an FDG-PET score ≤3 according to Lugano criteria. We utilized model-based simulations to compare two dosing regimens of epcoritamab monotherapy for each patient: the continuous regimen, which follows the clinically recommended protocol of ongoing treatment, and the fixed regimen, which stops treatment at cycle 8 day 28 (C8D28). A total of 100 virtual trials were performed to minimize the bias of randomness and the median result of the 100 virtual trials is presented. Population CR rates and individual duration of CR were compared between the two regimens. Patients' tumor characteristics and minimal residual disease (MRD) were explored as potential predictors of those who might benefit from the continuous regimen.
Results
This analysis included 165 aNHL patients, all of whom had at least two PET-CT scans. The developed model accurately captured epcoritamab PK, tumor growth dynamics, and changes of FDG-PET scores with robust parameter estimates. Tumor growth dynamics based on CT were used to predict changes in FDG-PET scores. The developed model, as well as individual parameter estimates, were further used to conduct treatment regimen simulations. Among 165 patients included in the simulation, 60 were predicted to achieve CR by C8D28 and were able to maintain CR for up to 5 years under the continuous treatment regimen. Under the fixed-duration regimen, 51 of the 60 CR patients were predicted to remain in CR, while 9 were predicted to experience disease relapses. These 9 patients exhibited faster tumor growth but slower responses to treatment, leading to less tumor shrinkage early on. The median tumor shrinkage at C3D28 was −59.8% for patients who were predicted to benefit from the continuous treatment regimen vs −92% for those who were not. Additionally, MRD reduction before C3D28 was less deep in patients who were predicted to benefit from the continuous treatment regimen. The benefits of continuous epcoritamab treatment post CR may arise from its ability to clear the residual tumor and MRD in these patients.
Conclusion
Our analysis demonstrated that the continuous treatment regimen of CD3xCD20 bispecific antibodies may prolong the duration of CR in 15% more aNHL patients vs the fixed-duration regimen. Patients who are predicted to benefit from continuous treatment exhibited shallower tumor shrinkage and less MRD reduction early on vs those who did not benefit. Further evaluation of this finding in clinical studies may be warranted.