592P Exposure response (ER) analysis for efficacy and safety 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 serous ovarian cancer. An ER analysis was conducted across 3 studies to understand the impact of MIRV, DM4, and S-methyl-DM4 (SmDM4) metabolite exposure on efficacy and safety in pts with FRα-positive tumors. A validated population pharmacokinetic model was used to derive the exposure metrics including area under the concentration-time curve (AUC) and trough concentration for eligible pts in 3 studies, 2 studies (n=445) with extensive sampling and a 3rd study (n=97) with sparse sampling. The objective response rate (ORR) and progression free survival (PFS) were analyzed as well as adverse events (AE) of grade 2 or higher. Logistic regression and Cox proportional hazard approach were used, and covariate search was performed. The AUC and trough concentration of MIRV were found to correlate with efficacy. Higher exposure to MIRV resulted in higher probability of therapeutic response in both study pools in terms of ORR (p<0.01) and PFS (p<0.03). In the safety analysis, MIRV AUC was the exposure parameter that correlated best with ocular AEs. The incident rate of grade 2+ ocular AEs increased with increasing MIRV exposure (p<0.01 for the pooled analysis). The overall ER relationship for peripheral neuropathy was flat. MIRV exposure did not have a significant impact on pneumonitis. The exposures of the payload, DM4, or the metabolite, SmDM4, were not found to associate with either efficacy or safety. Covariates, including patient demographics and clinical laboratory test results, identified in this model had limited impact of efficacy and safety, and are likely not of clinical significance. ER analysis demonstrated that both efficacy and probability of ocular toxicity correlate with exposure of MIRV. The analyses support the final recommended dose of 6 mg/kg based on adjusted ideal body weight every 3 weeks with balanced efficacy and safety.