Anne-Gaelle Dosne1, Xia Li1, Man Melody Luo2, Ivo Nnane2, Tobias Kampfenkel3, Robin Carson4, Himal Amin5, Honghui Zhou2, Yu-Nien Sun2,6, and Yan Xu2,6,7
1Clinical Pharmacology and Pharmacometrics, Janssen Research & Development LLC, Beerse, Belgium; 2Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, LLC, Spring House, PA, USA; 3Janssen Research & Development, LLC, Leiden, The Netherlands; 4Janssen Research & Development, LLC, Spring House, PA, USA; 5Janssen Research & Development, LLC, Raritan, NJ, USA; 6these authors are not Janssen employees anymore, their affiliation at the time of the analysis is listed; 7Simcere Pharmaceuticals, Cambridge, MA USA.
Objectives: Daratumumab, a human IgG monoclonal antibody targeting CD38, has been approved to treat patients with multiple myeloma (MM). We aimed to develop a population pharmacokinetic (PPK) model to characterize the pharmacokinetics (PK) of intravenously (IV) and subcutaneously (SC) administered daratumumab in combination with dexamethasone and pomalidomide (Pd) in patients with relapsed or refractory multiple myeloma (RRMM), and also conduct an exposure-response (E-R) analysis to explore E-R relationships for efficacy and selected treatment-emergent adverse events (TEAEs).
Methods:
The PPK analysis included serum concentrations of daratumumab from the D-Pd cohorts of studies APOLLO [1] and EQUULEUS [2]. APOLLO was an open-label, phase 3 study with patients randomized to Pd with or without daratumumab [daratumumab treated patients were at a dose of 1800 mg SC or 16 mg/kg IV administered once weekly for 8 weeks, followed by every 2 weeks (Q2W) for 16 weeks, and then every 4 weeks]. EQUULEUS was an open-label phase 1b study of daratumumab in combination with various backbone regimens, including D-Pd cohort for subjects with the same IV dosing regimen as the one for APOLLO D-Pd. The E-R analysis for efficacy and safety was based on data from APOLLO only.
The PPK analysis was performed using nonlinear mixed-effects modeling (NONMEM 7.4.1). Exploratory analysis, diagnostic graphics, and post-processing of NONMEM analysis results were carried out using R. A previously developed PPK structural and covariate model for daratumumab IV/SC monotherapy was used to fit the PK data of daratumumab in patients with RRMM who received D-Pd combination therapy [3]. Covariates were evaluated in the PPK model. Model-based simulated trough concentration at Cycle 3 Day 1 (Ctrough,C3D1) were also compared between covariate subgroups. Model evaluation was based on objective function value, acceptable parameter precision, and goodness-of-fit.
The efficacy analysis was performed by plotting Kaplan-Meier curves of progression-free survival among PK exposure quartiles subgroups (i.e., first peak concentration, first trough concentration, maximum trough concentration) compared to control group. The rates of selected TEAEs among PK exposure quartiles subgroups were numerically compared to those of the control group.
Results:
The PPK analysis was based on 1,146 daratumumab PK samples from 239 patients from APOLLO (n=140) and EQUULEUS (n=99). Observed PK data of daratumumab were well described by a 2-compartment PPK model with first-order absorption and parallel nonspecific linear clearance (CL) and Michaelis-Menten elimination. The decrease of total target receptor (CD38) over time was empirically characterized by an exponential reduction of maximum capacity Vmax over time. The model was parameterized in terms of CL (0.00432 L/h), central volume of distribution V1 (4.36 L), peripheral volume of distribution V2 (2.80 L/h), inter-compartmental clearance Q (0.00814 L/h), first-order absorption rate Ka (0.012 h-1), Vmax (1.47 mg/h), first-order rate for decrease of Vmax over time (KDES, 0.000282 h-1), and Michaelis-Menten constant (Km, 3.81 μg/mL). The SC bioavailability was fixed to 0.689 based on previous PPK monotherapy analysis.
The current PPK analysis confirmed the previously identified statistically significant effects of body weight, albumin concentration and type of myeloma on linear clearance, as well as of body weight and sex on central volume of distribution. No other covariates were identified. The statistically significant covariates were not clinically relevant, with a difference of <20% on Ctrough,C3D1 between covariate subgroups. Therefore, no dose adjustment is recommended based on any of these factors.
The E-R dataset contained data from 290 patients from APOLLO (D-Pd, n=140; Pd, n=150). The E-R analysis showed statistically significant improvements in PFS for patients in D-Pd group compared with control group. PFS improvements were consistent across clinically important subgroups and PK exposure metrics.
There was no apparent increase in TEAE rates with increasing daratumumab PK exposures for IRRs, thrombocytopenia, anemia, neutropenia, and infections (all grades and grades ≥3).
Conclusions:
The PPK and E-R analyses support the daratumumab SC 1,800 mg dose regimen in combination with Pd for the treatment of patients with RRMM. No body weight-based dose adjustment is recommended for efficacy or safety reasons.
References:
[1] Dimopoulos MA, Terpos E, Boccadoro M, et al. APOLLO Trial Investigators. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021 Jun;22(6):801-812. doi: 10.1016/S1470-2045(21)00128-5. PMID: 34087126.
[2] Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130(8):974-981. doi:10.1182/blood-2017-05-785246. [3] Luo MM, Usmani SZ, Mateos MV, et al. Exposure-Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients. J Clin Pharmacol. 2021;61(5):614-627. doi:10.1002/jcph.1771
Reference: PAGE 30 (2022) Abstr 9969 [www.page-meeting.org/?abstract=9969]
Poster: Drug/Disease Modelling - Oncology