Pooneh Soltantabar1, Jennifer Hibma2, Diane Wang1, Akos Czibere1, Anne Hickman1, Mohamed Elmeliegy1
1 Oncology Research and Development, Pfizer Inc 2 Research and Development, Pfizer Inc
Introduction: Elranatamab (ELRA) is a heterodimeric humanized bispecific antibody approved for treatment of patients with relapsed/refractory multiple myeloma (RRMM). ELRA is comprised of one arm that binds to B-cell maturation antigen (BCMA) and another arm that binds to the cluster of differentiation 3 (CD3). The pivotal Phase 2 MagnetisMM-3 trial (NCT04649359) supported the effectiveness of ELRA as a treatment for patients with RRMM with a manageable safety profile.Higher ELRA exposure was shown to be associated with incidence of any grade and grade ≥ 2 cytokine release syndrome leading to the optimization of elranatamab priming dose regimen1. The relationship between elranatamab exposure and selected adverse events (AEs) were previously reported using logistic regression analysis. This analysis showed a relatively flat relationship between elranatamab exposure (concentration at time of the event, Cavg, event) and selected adverse events (AEs) 2. Cavg, event was used to account for dose modifications. The potential bias introduced by the causal dependence of Cavg, event on the event time3 motivated conducting the exposure-response (ER) analysis using a time-varying Cox Proportional Hazard (PH) analysis.
Objective: To assess the ER relationship between ELRA exposure and selected safety endpoints and identifying potential significant covariates affecting the ER relationship.
Methods: The ER-safety analysis of ELRA monotherapy was performed using pooled data from 4 studies: MagnetisMM-1 (first-in-human Ph1, NCT03269136), MagnetisMM-2 (Japan Ph1, NCT04798586), MagnetisMM-3 (Ph2), and MagnetisMM-9 (Ph1/2, NCT05014412). These studies included a dose range of 0.1 to 50 μg/kg IV and 80 to 1000 μg/kg (6 to 76 mg) QW SC allowing for characterization of ELRA exposure-safety profile across a wide dosing range.
Selected safety endpoints (namely Grade ≥ 3 (G3+) infections, G3+ neutropenia, as well as AEs leading to dose modifications) were analyzed via time varying Cox PH analysis. To account for the difference in time to incidence of AEs and for potential ELRA dosing delays, time-varying average ELRA concentration (Cav,t) was used as the PK metric in this analysis 4. First, visual examination was conducted via comparisons of Cave,t values in patients with or without the specified event at each time point when the events occurred. Univariable Cox PH model was used to quantify the effects of ELRA Cave,t and other baseline covariates on safety endpoints (p-value=0.05). The significant covariates identified from the univariable analysis were simultaneously included in the multivariable Cox PH analysis. ELRA exposure measure Cave,t was carried forward to the multivariate analyses. Lastly, final model was developed by Cox PH analysis of significant covariates/exposure metric identified in the multivariable step (p-value=0.01). Proportional hazard assumption was tested using Schoenfeld residuals.
Results: Out of 324 participants treated with elranatamab monotherapy, G3+ neutropenia, G3+ infection, and dose modifications was observed in 48.1%, 41.7% and 72.5%, respectively.
No trend associating these safety endpoints with Cave,t was observed in the longitudinal plots. Additionally, Cox PH analysis demonstrated that Cave,t was not significantly associated with these safety endpoints. The final model showed that higher baseline bilirubin was associated with higher probability of G3+ neutropenia (p-value=0.005; Hazard Ratio 1.6, 95% CI 1.15-2.22). Additionally, final models showed that neither the exposure metric, nor any of the covariates were significant for G3+ infection and AEs leading to dose modifications. Proportional hazard assumption was confirmed using Schoenfeld residuals.
Conclusion: No statistically significant relationship was observed between ELRA exposure, the incidence of G3+ AEs of neutropenia/infection and AEs leading to dose modifications, as assessed through the graphical diagnostic of Schoenfeld residual and statistical test. ELRA demonstrated a flat exposure-safety profile. This finding together with the positive exposure-efficacy relationship for ELRA3 collectively support a meaningful clinical benefit and a favorable benefit-risk observed for the recommended dosing regimen of ELRA at the 76 mg weekly dosing regimen.
References:
[1] Elmeliegy, M., Viqueira, A., Vandendries, E., Hickman, A., Hibma, J., Lon, H.K., Piscitelli, J., Soltantabar, P., Wang, D., Jiang, S. and Finn, G., 2022. Dose optimization to mitigate the risk of CRS with elranatamab in multiple myeloma. Blood, 140(Supplement 1), pp.7174-7175.
[2] Soltantabar, P., Irby, D., Hibma, J., Wang, D., Williams, J., Czibere, A., Viqueira, A., Hickman, A. and Elmeliegy, M., 2023. P-315 Elranatamab exposure-safety analysis in patients with relapsed/refractory multiple myeloma: analysis from MagnetisMM studies. Clinical Lymphoma Myeloma and Leukemia, 23, pp.S211-S212.
[3] Wiens, M.R., French, J.L. and Rogers, J.A., 2024. Confounded exposure metrics. CPT: Pharmacometrics & Systems Pharmacology, 13(2), p.187.
[4] Hibma, J., Elmeliegy, M., King, L., Gifondorwa, D., Wang, D., Williams, J., 2023, Population Pharmacokinetic Analysis of Elranatamab in Patients with Multiple Myeloma. Population approach group Europe
Reference: PAGE 32 (2024) Abstr 11081 [www.page-meeting.org/?abstract=11081]
Poster: Drug/Disease Modelling - Oncology