H. Maxime Lagraauw

Exposure–response relationships of mirvetuximab soravtansine in patients with folate receptor‐α‐positive ovarian cancer: Justification of therapeutic dose regimen

AimsThis study aimed to investigate exposure–response (ER) relationships in efficacy and safety for mirvetuximab soravtansine (MIRV) which is a first‐in‐class antibody–drug conjugate approved for the treatment of folate receptor‐α‐positive platinum‐resistant ovarian cancer.MethodsMIRV was characterized in 4 clinical studies. Exposure metrics for MIRV, its payload and a metabolite were derived from a population pharmacokinetic model. Efficacy was analysed in MIRV‐treated patients (n = 215) in a recent confirmatory, randomized, chemotherapy‐controlled MIRASOL trial and safety was evaluated in patients pooled across all 4 clinical studies (n = 757).ResultsIn the MIRASOL trial (NCT04209855), MIRV demonstrated significant benefit over chemotherapy in progression‐free survival (PFS), objective response rate (ORR) and overall survival (OS). The most common adverse events (AEs) included ocular disorders, peripheral neuropathy and pneumonitis. For PFS, ORR and OS, the trough concentration of MIRV was the predictor consistently found in ER models for efficacy. In contrast, for ocular AEs (as well as the time to onset of ocular AEs) and peripheral neuropathy, the area under the concentration–time curve (AUC) of MIRV was identified as the exposure metric in ER models for safety. No exposure parameters were found to correlate with pneumonitis. Covariates in all models did not show clinically meaningful impact on efficacy or safety. Logistic regression models for ORR and ocular AEs based on AUC of MIRV were used to justify the clinical dose regimen approved for MIRV.ConclusionThe trough concentration of MIRV correlated with efficacy whereas the AUC of MIRV was associated with major AEs. The ER relationships supported the selected therapeutic dose regimen.

Population pharmacokinetics of mirvetuximab soravtansine in patients with folate receptor‐α positive ovarian cancer: The antibody–drug conjugate, payload and metabolite

AimsMirvetuximab soravtansine is a first‐in‐class antibody–drug conjugate recently approved for the treatment of folate receptor‐α positive ovarian cancer. The aim of this study was to develop a population pharmacokinetic model to describe the concentration–time profiles of mirvetuximab soravtansine, the payload (DM4) and a metabolite (S‐methyl‐DM4).MethodsMirvetuximab soravtansine was administered intravenously from 0.15 to 7 mg/kg to 543 patients with predominantly platinum‐resistant ovarian cancer in 3 clinical studies, and the plasma drug concentrations were analysed using a nonlinear mixed‐effects modelling approach. Stepwise covariate modelling was performed to identify covariates.ResultsWe developed a semi‐mechanistic population pharmacokinetic model that included linear and nonlinear routes for the elimination of mirvetuximab soravtansine and a target compartment for the formation and disposition of the payload and metabolite in tumour cells. The clearance and volume of the central compartment were 0.0153 L/h and 2.63 L for mirvetuximab soravtansine, 8.83 L/h and 3.67 L for DM4, and 2.04 L/h and 6.3 L for S‐methyl‐DM4, respectively. Body weight, serum albumin and age were identified as statistically significant covariates. Exposures in patients with renal or hepatic impairment and who used concomitant cytochrome P450 (CYP) 3A4 inhibitors were estimated.ConclusionThere is no need for dose adjustment due to covariate effects for mirvetuximab soravtansine administered at the recommended dose of 6 mg/kg based on adjusted ideal body weight. Dose adjustment is not required for patients with mild or moderate renal impairment, mild hepatic impairment, or when concomitant weak and moderate CYP3A4 inhibitors are used.