Mirvetuximab Soravtansine: Mechanism of Action, Clinical and Translational Science

Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate (ADC) composed of the DM4 payload conjugated to a folate receptor α (FRα)-targeting antibody via the cleavable sulfo-SPDB linker. MIRV targets and binds to FRα with high affinity and specificity, releasing the DM4 payload intracellularly following MIRV-FRα complex internalization and degradation. DM4 and its metabolite S-methyl-DM4 suppress microtubule dynamic instability, which triggers cell cycle arrest and apoptosis. Selective FRα-overexpression in ≥ 90% of epithelial ovarian tumor cells and its ability to internalize large molecules make it a highly attractive ADC target for epithelial ovarian cancers (including primary peritoneal and fallopian tube cancers). Although up to 80% of patients initially respond to platinum-based therapies, the majority of tumors will recur and become platinum-resistant. Unfortunately, platinum-resistant ovarian cancer (PROC) carries a poor prognosis with an overall survival of 12-14 months from the time of platinum-resistance, and prior to MIRV approval in 2022, little had changed in treatment options for decades. The MIRV Phase 3 registrational trial (MIRASOL) showed superiority of MIRV vs. chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan) in patients with high (≥ 75%) FRα-expression PROC, showing an objective response rate of 42% versus 16%, a median progression-free survival of 5.6 versus 4.0 months, and an overall survival of 16.5 versus 12.8 months. Here, we briefly review MIRV mechanism of action, pharmacokinetics, pharmacodynamics, and key clinical efficacy and safety data.