Exposure-Response Relationships of Mirvetuximab Soravtansine in Patients
with Folate Receptor-α Positive Ovarian Cancer: Justification of
Therapeutic Dose Regimen
Abstract
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.