Hoai-Thu Thai (1), Kimiko Koiwai (2), Florence Suzan (3), Semiond Dorothée (4)
(1) Sanofi, Data and Data Sciences, Translational Disease Modeling, Gentilly, France (2) Sanofi, Translational Medicine and Early Development, Modeling & Simulation, Vitry-sur-Seine, France (3) Sanofi, Oncology Development, Vitry-sur-Seine, France (4) Sanofi, Translational Medicine and Early Development, Cambridge, MA, USA
Introduction: Intravenous (IV) isatuximab (Isa) plus pomalidomide-dexamethasone (Pd) is approved for the treatment of patients with relapsed/refractory multiple myeloma (RRMM). Subcutaneous (SC) administration within minutes would optimize convenience of administration compared to the approved IV route. A Phase 1b study (NCT04045795) evaluated safety, pharmacokinetics (PK), and efficacy of SC Isa plus Pd vs IV Isa plus Pd [1].
Objectives: a) to characterize the effects of Isa plus Pd on serum M-protein and progression-free survival (PFS) in the Phase 1b study, comparing the IV vs SC route; b) to perform simulations and compare the benefits of SC Isa dosing regimens (1000 or 1400 mg) versus the approved IV Isa dose of 10 mg/kg, every week for 4 weeks then every 2 weeks (QW/Q2W) in combination with Pd.
Methods: 40 of 56 RRMM patients from the Phase 1b study were included in this analysis. Patients were randomized to SC by infusion pump (IP) 1000 mg and IV 10 mg/kg or to IP 1400 mg and IV. In the expansion cohort, SC Isa administration via on-body delivery system (OBDS) was evaluated at the recommended Phase 2 dose of 1400 mg. We developed a joint model of serum M-protein dynamics and PFS similar to the model previously published with ICARIA-MM data [2] to include the SC route in the PK model. The relationships between baseline covariates and model parameters were evaluated using univariate analysis followed by the automatic covariate selection procedure based on the correlation tests (COSSAC) [3]. External validation was performed using the IV Isa plus Pd arm of the ICARIA-MM trial. Trial simulations were then conducted using the ICARIA-MM patient population in the Isa plus Pd arm (N=128) to compare the benefits of SC Isa 1000 mg and 1400 mg versus the approved IV dose, in combination with Pd. Model parameters were estimated using the SAEM algorithm implemented in Monolix2023R1; simulations were performed using SimulX2023R1 and R version 4.2.0.
Results: The developed joint model described well the observed serum M-protein and PFS data in the Phase 1b study and predicted reasonably well the outcome of the ICARIA-MM treatment arm in the external validation step. The model identified instantaneous changes (slope) in serum M-protein as the best on-treatment predictor of PFS and baseline patient characteristics impacting serum M-protein kinetics (patient cohort on the baseline levels, alanine aminotransferase (ALT) on the killing rate, number of prior lines on the resistance rate). No covariates were found to be significant in the PFS model. Patients with less than 3 lines tended to have greater resistance rate to the treatment, resulting in faster tumor regrowth (i.e re-increase in serum M-protein) and shorter PFS. However, this effect was correlated to the presence of extramedullary plasmacytoma. Patients with high ALT tended to have lower M-protein shrinkage rate and patients in the expansion cohort had lower baseline M-protein. Nevertheless, these baseline covariates (ALT, cohort) had no impact on PFS.
The simulations of 1000 ICARIA-MM-like trials suggested that SC Isa 1400 mg would induce a greater decrease in serum M-protein from baseline at week 8 ( -72% vs -66%) and prolong median PFS of 2.3 weeks on average versus IV 10 mg/kg, in combination with Pd. A lower dose of SC Isa, 1000 mg, would induce a slightly lower or similar decrease in serum M-protein from baseline at week 8 and a similar median PFS compared to IV 10 mg/kg. The simulations suggest that SC Isa 1400 mg would be at least as efficacious as the approved IV dose of 10 mg/kg with prolonged median PFS predicted in 90% of the simulated trials. In addition, SC Isa 1400 mg administered via OBDS has shown a safety profile consistent with IV administration [1].
Conclusion: Our results retrospectively support the selection of the Isa SC dose of 1400 mg for the treatment of patients with RRMM in combination with Pd. These findings need to be confirmed with the results of the ongoing Phase 3 SC Isa trial.
References:
[1] Quach H, et al. Subcutaneous (SC) isatuximab administration by an on-body delivery system (OBDS) in combination with pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM): Interim phase 1b study results. J Clin Oncol. 40, 16 (2022).
[2] Thai H, et al. Joint modelling and simulation of M-protein dynamics and progression-free survival for alternative isatuximab dosing with pomalidomide/dexamethasone. Br J Clin Pharmacol. 88, 2052–2064 (2022).
[3] Ayral G, et al. A novel method based on unbiased correlations tests for covariate selection in nonlinear mixed effects models: The COSSAC approach. CPT Pharmacometrics Syst Pharmacol. 10, 318–329 (2021).
Reference: PAGE 32 (2024) Abstr 11129 [www.page-meeting.org/?abstract=11129]
Poster: Drug/Disease Modelling - Oncology