Aims: This 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. Methods: MIRV was characterized in 4 clinical studies. Exposure metrics for MIRV, its payload and a metabolite were derived from a population pharmacokinetic model. Efficacy was analyzed 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). Results: In the MIRASOL trial, 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) 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 were used to justify the clinical dose regimen approved for MIRV. Conclusions: The trough concentration of MIRV correlated with efficacy whereas the AUC was associated with major AEs. The ER relationships supported the selected therapeutic dose regimen.

Aims: Mirvetuximab soravtansine is the first-in-class antibody-drug conjugate approved in November 2022 for the treatment of folate receptor-α positive ovarian cancer. The aim of this study was to develop a population pharmacokinetic (PK) model to describe the concentration-time profiles of mirvetuximab soravtansine, the payload (DM4) and a metabolite (S-methyl-DM4). Methods: Mirvetuximab soravtansine was administered intravenously from 0.15 to 7 mg/kg to 543 patients with predominantly platinum-resistant ovarian cancer in three clinical studies, and the plasma drug concentrations were analyzed using a nonlinear mixed-effects modelling approach to estimate the PK parameters, inter-individual variabilities, and residual errors. Stepwise covariate modelling was performed to identify covariates. Results: We developed a semi-mechanistic population PK 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 tumor cells. The model adequately described the concentration-time profiles for the three analytes. Patient body weight, serum albumin, and age were identified as the major covariates. Exposures in patients with renal or hepatic impairment were estimated. The effect of inhibition of cytochrome P450 (CYP) 3A4 on drug exposures was also evaluated. Conclusions: There 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. The model also showed that 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.