Yaping Tu

and 8 more

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.