Population pharmacokinetics of belantamab mafodotin in relapsed or refractory multiple myeloma patients with severe renal impairment
Theodoros Papathanasiou (1), Courtney Nugent (2,5), Seema Shafi-Harji (3), Michael Arning (4), Geraldine Ferron-Brady (5), Herbert Struemper (6)
(1) Clinical Pharmacology Modeling & Simulation, GSK, Baar, Switzerland (2) Certara, Princeton, NJ, USA (3) Oncology Clinical Development, GSK, Stevenage, UK (4) Oncology Clinical Development, GSK, Upper Providence, PA, USA (5) Clinical Pharmacology Modeling & Simulation, Upper Providence, PA, USA (6) Clinical Pharmacology Modeling & Simulation, Durham, NC, USA
Objectives:
Belantamab mafodotin is an antibody-drug conjugate (ADC) consisting of an afucosylated humanized anti-B‐cell maturation antigen (BCMA) monoclonal antibody (mAb) conjugated to the intracellular microtubule disruptor cysteine-monomethyl auristatin-F (cys-mcMMAF), intended for the treatment of multiple myeloma (MM) [1].
Multiple studies have been conducted to evaluate the safety, tolerability, efficacy, and pharmacokinetics (PK) of belantamab mafodotin in patients with MM. Renal impairment is a frequent and major complication of MM [2] and MM patients with mild to moderate renal impairment have been included in clinical trials. A recent trial has included patients with severe renal impairment. The objective of the present work was to evaluate using population PK analyses, whether the PK profile of ADC or cys-mcMMAF following 2.5 mg/kg i.v. belantamab mafodotin administration is altered in patients with severe renal impairment who were evaluated in a dedicated renal impairment study (DREAMM-12).
Methods:
ADC and cys-mcMMAF plasma concentrations and baseline patient characteristics were available from DREAMM-12 (NCT04398745), an ongoing Phase 1 study of belantamab mafodotin monotherapy in patients with RRMM, who had normal or mildly impaired renal function (Group 1, n=8, estimated glomerular filtration rate [eGFR] ≥60 mL/min) or severely impaired renal function (Group 2, n=8 (eGFR between 15 and 29 mL/min).
The population PK of ADC and cys-mcMMAF has been previously described with compartmental models, developed using a sequential modeling approach [3]. ADC PK was described by a linear, two-compartment model, with a time-varying decrease in clearance, and baseline soluble BCMA, immunoglobulin G (IgG), albumin, and total body weight as covariates. Cys-mcMMAF PK was described with a linear two-compartment model linked to ADC. Cys-mcMMAF input rate was governed by deconjugation/intracellular proteolytic degradation of ADC, baseline soluble BCMA and IgG as covariates. As an exploratory post-hoc analysis, these previously developed population PK models were applied to the DREAMM-12 PK data as previously described [4]. The dataset consisted of PK observations of patients in Group 1 and Group 2 that were matched in terms of baseline body weight and albumin concentration. Population and individual empirical bayes estimates (EBEs) of ADC and cys-mcMMAF concentrations were obtained using NONMEM (v.7.3) [5]. EBE correlations with key covariates, such as eGFR were graphically explored. Model-derived concentration profiles were used to compute individual ADC Cmax and AUC(0-504h), as well as cys-mcMMAF Cmax and AUC(0-168h), and the model-derived summary exposure metrics were compared across Group 1 and Group 2.
Results:
The previously developed population PK models predicted ADC and cys-mcMMAF plasma concentrations well with no consistent bias. Using the population PK approach, exposure parameters were derived for additional patients whose PK profiles were disqualified for standard noncompartmental (NCA) PK analysis. Graphical explorations did not reveal a trend between the EBEs for clearance and central volume of distribution and eGFR for ADC and cys-mcMMAF. ADC and cys-mcMMAF Cycle 1 model-derived exposure metrics were comparable, with overlapping 95% confidence intervals across Group 1 and Group 2. Model-derived geometric mean of ADC Cmax and AUC(0-504h) were 47.8 μg/mL (Group 1), 40.8 μg/mL (Group 2), and 4,337 μg.h/mL (Group 1) and 3,606 μg.h/mL (Group 2), respectively. Model-derived geometric mean of cys-mcMMAF Cmax and AUC(0-168h) were 1.1 ng/mL (Group 1), 0.64 ng/mL (Group 2), and 4.36 ng.h/mL (Group 1) and 2.78 ng.h/mL (Group 2), respectively. The model-based exposure summaries were consistent with the results from the corresponding NCA analyses.
Conclusions:
Model derived exposure metrics for ADC and cys-mcMMAF were comparable between Group 1 and Group 2. Patients with severe renal impairment did not have higher ADC or cys-mcMMAF exposures as compared to RRMM patients with normal or mildly impaired renal function. The presented PK analysis suggests that the starting dose or schedule of belantamab mafodotin does not need to be adjusted for patients with severe renal impairment.
Funding: GSK (Study 209626). Drug linker technology licensed from Seagen Inc.; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.
References:
[1] Lonial, S. et al. (2020). Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. The Lancet Oncology, 21(2), 207–221. https://doi.org/10.1016/S1470-2045(19)30788-0
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[3] Rathi, C. et al. (2021). Population pharmacokinetics of belantamab mafodotin, a BCMA-targeting agent in patients with relapsed/refractory multiple myeloma. CPT: Pharmacometrics and Systems Pharmacology, 10(8), 851–863.
[4] Carreno F. et al. Predictive Performance of Belantamab Mafodotin Population Pharmacokinetics Model in Earlier-Line Multiple Myeloma Patients. ACoP13 (2022) PMX-366 [www.go-acop.org/?abstract=366]
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