Rationale for the Clinical Use of Less Frequent Dosing of Mogamulizumab for T-Cell Lymphomas Using Population Pharmacokinetic and Exposure Response Analysis

Abstract

▪Background: CC chemokine receptor 4 (CCR4) is expressed on several T cell subsets and is implicated in the pathogenesis of a variety of leukemias and lymphomas. Mogamulizumab is a humanized monoclonal antibody targeting CCR4 receptors and is indicated for treatment of adult patients with cutaneous T-cell lymphoma (relapsed or refractory mycosis fungoides or Sézary syndrome). The objectives of these analyses were to (1) develop a population pharmacokinetics (PPK) model to characterize mogamulizumab PK following administration to subjects who have lymphomas or solid tumors, (2) evaluate patient covariates that influence the variability in PK, (3) simulate mogamulizumab PK at 2 mg/kg every four weeks (Q4W) dosing and compare with the PK at 1 mg/kg every two weeks (Q2W) dosing and (4) assess the exposure-response (ER) relationship between mogamulizumab exposures and adverse events (AEs). A Phase 2 clinical study is ongoing to obtain PK, efficacy, and safety data for 2 mg/kg Q4W dosing (NCT04745234).Methods: Plasma or serum pharmacokinetic data from 525 subjects with cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), adult T-cell leukemia-lymphoma (ATL), or solid tumors were included in this analysis. Mogamulizumab was administered over 0.01 mg/kg to 3 mg/kg dose range as mono- or combination-therapy. Nonlinear mixed effects modeling was used to develop a base PPK model followed by covariate evaluation. Simulations were performed to estimate exposure metrics to support ER analyses and to compare 2 mg/kg Q4W and 1 mg/kg Q2W dosing scenarios following four 1 mg/kg weekly doses in the first cycle of treatment. Comparisons between mogamulizumab exposures and grade 3 and grade 4 AEs were conducted.Results: A two-compartment PPK model with linear elimination and log-normal variability on clearance and the volumes of distribution of the central and peripheral compartments, described the PK data. Body weight, albumin, and tumor type were identified as statistically significant covariates affecting mogamulizumab exposure. Other covariates that were tested but did not demonstrate statistically significant effect on mogamulizumab exposure included age, race, creatinine clearance, degree of CCR4 expression, combination- vs. mono-therapy, CTCL subtype (when applicable), and mild hepatic impairment. The PK simulations demonstrated that the overall exposures (AUC ss) achieved with mogamulizumab 2 mg/kg Q4W dosing were comparable to mogamulizumab 1 mg/kg Q2W dosing, with C max predicted to be 47% greater and C min to be 29% lower. Evaluations of dose and exposure (AUC ss, C max, C min) vs. incidence of grade 3 and grade 4 AEs showed no relationship.Conclusions: The PPK model adequately characterized the mogamulizumab PK over the doses ranging from 0.01 to 3 mg/kg. There was no relationship between the exposure of mogamulizumab and the emergence of grade 3 or grade 4 AEs across the dose range explored. Thus, the mogamulizumab 2 mg/kg Q4W dosing is not expected to lead to increased incidences of grade 3 and grade 4 AEs. From a PK and safety perspective, this analysis supports 2 mg/kg Q4W Mogamulizumab as an appropriate alternative dosing strategy to the approved, 1 mg/kg Q2W, dosing posology in T-cell lymphomas.Acknowledgements: We would like to express special appreciation to Dr. Roland Meier, MD, PhD, for sponsoring this abstract. DisclosuresMehta: Kyowa Kirin: Current Employment. Patel: Kyowa Kirin: Current Employment. Vuppugalla: Kyowa Kirin: Current Employment. Tudor: Kyowa Kirin: Current Employment. Dwyer: Kyowa Kirin: Current Employment; Bristol Myers Squibb: Current Employment. Hruska: Viatris: Current equity holder in publicly-traded company; Viking: Current equity holder in publicly-traded company; Durect: Current equity holder in publicly-traded company; CymaBay: Current equity holder in publicly-traded company; Takeda: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company; Johnson & Johnson: Current equity holder in publicly-traded company; GlaxoSmithKline: Current equity holder in publicly-traded company; Genmab: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; Biohaven: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company; Bristol Myers Squibb: Current equity holder in publicly-traded company; Kyowa Kirin: Current Employment. Marsteller: Kyowa Kirin: Current Employment. OffLabel Disclosure:Yes. Mogamulizumab is a CCR4-directed monoclonal antibody indicated for the treatment of adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome after at least one prior systemic therapy - new dosing regimen under examination.