Exposure-Response Analyses and Disease Modeling for Selection and Confirmation of Optimal Dosing Regimen of Isatuximab in Combination Treatment in Patients with Multiple Myeloma

Background: Isatuximab (Isa) is an anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells through direct tumor targeting and immune cell engagement. Exposure-Response (E-R) analysis and disease modelling of tumor burden were performed to evaluate the relationship between Isa exposure and efficacy outcomes. This analysis also supports the Isatuximab dosing regimen selection/confirmation when administered in combination in relapsed/refractory multiple myeloma (RRMM) patients. Methods: To determine the optimal dose for the Phase 3 ICARIA-MM study, E-R analyses were conducted in 44 and 52 RRMM evaluable patients from two Phase 1 trials of Isa in combination with pomalidomide/dexamethasone (Pd) (NCT02283775) or with lenalidomide/dexamethasone (Rd) (NCT01749969), respectively. Isa was administered intravenously at doses from 3 to 20 mg/kg every 2 weeks or weekly for 4 weeks then every 2 weeks (QW/Q2W). In the E-R analyses, several Isa exposure parameters were tested to evaluate if they were predictors of response (partial response [PR] or better). Baseline covariates were also considered in the model to evaluate potential confounding effects. In addition, a second type of analysis was performed on 2 pooled datasets of 153 (single agent and combination with Pd) and 162 (single agent and combination with Rd) evaluable RRMM patients: disease response was also captured by modeling the dynamics of the serum M-protein using a joint model of tumor growth inhibition and drop-out. Trial simulations were then performed to evaluate different dosing regimens of interest. To confirm the dose, E-R analyses were conducted in 297 evaluable RRMM patients from the phase 3 trial (ICARIA-MM; NCT02990338) comparing Isa-Pd (N=148) and Pd (N=149). Isa was administered intravenously at 10 mg/kg QW/Q2W in the Isa-Pd arm. Cox and Weibull (Progression-Free Survival [PFS]) or logistic regression (overall response rate [ORR]) models were used. Results: In the two combination Phase 1 trials, Isa appeared to be well tolerated with no clear dose response relationship between 10 and 20 mg/kg. E-R analyses suggested that higher Isa exposure represented by log Ctrough at 4 weeks (CT4W) was associated with increased ORR. Both models predicted an increased ORR with decreased beta-2 microglobulin and lower number of prior lines of therapy (Rd only), together with higher log CT4W. Clinical trial simulations showed that the probability of success to reach the targeted ORR