605P Population pharmacokinetic (PK) analysis of mirvetuximab soravtansine (MIRV) in patients with folate receptor α (FRα)-positive cancer

Abstract

MIRV is a first-in-class antibody-drug conjugate comprising an FRα-binding antibody, cleavable linker, and maytansinoid DM4 payload for patients (pts) with FRα-positive, high grade serious ovarian cancer (OC). Analysis was conducted across 3 studies to understand the impact of pt characteristics on the PK parameters of MIRV, DM4, and S-methyl-DM4 (SmDM4) metabolite in pts with FRα-positive tumors. A base model was developed for MIRV followed by a stepwise covariate search. Structural components were added for DM4 and SmDM4 concentration data while fixing MIRV PK parameters. The final semi-mechanistic model accommodated saturable elimination of MIRV and the payload metabolite. Model construction was based on 2 studies (n=445) with extensive sampling and validated in a 3rd study (n=98) with sparse sampling. The evaluated doses ranged from 0.15 mg/kg to 7 mg/kg total body weight, including the final recommended dose of 6 mg/kg adjusted ideal body weight (AIBW) every 3 weeks, which was administered to 87.8% of total pts. The population PK model predicted a low clearance (CL), small volume of distribution (Vd), and long elimination half-life (t1/2) for MIRV. Statistically significant covariates include AIBW, serum albumin, and age. Tumor FRα expression was not a significant covariate. AIBW showed an impact on CL and Vd. Albumin showed significant effect on CL but not on Vd. Age did not impact CL and was found to be a minor covariate on Vd. For 6 mg/kg AIBW, the effects of these covariates on the exposures to MIRV do not require dose adjustment. With a terminal elimination t1/2 of 115 hrs (4.8 days), the steady state can be reached in ∼24 days. Mild or moderate renal impairment and mild hepatic impairment did not significantly alter PK. Coadministration with weak, moderate, and strong cytochrome P450 3A4 (CYP3A4) inhibitors did not have clinically meaningful effects on PK parameters for MIRV, DM4, or SmDM4; CYP3A4 inducers were not evaluated. Population PK analysis supports 6 mg/kg AIBW dosing of MIRV, with exposure to MIRV, DM4, and SmDM4 maintained within the target range. Dosing adjustments would not be required for mild or moderate renal or mild hepatic impaired population.