Evaluation of Prophylactic Corticosteroid Eye Drop Use in the Management of Corneal Abnormalities Induced by the Antibody–Drug Conjugate Mirvetuximab Soravtansine

Abstract

Purpose: Reversible, low-grade ocular adverse events (AE) are associated with administration of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeted antibody-drug conjugate undergoing phase III clinical evaluation in platinumresistant ovarian cancer. This study investigated the underlying mechanisms of ocular toxicity and evaluated primary prophylactic use of corticosteroid eye drops in patients receiving mirvetuximab soravtansine. Patients and Methods: Target expression in the human eye was determined by IHC. The ocular toxicity profile of mirvetuximab soravtansine was assessed preclinically using Dutch-Belted rabbits. In a phase I clinical study, patients with ovarian cancer were treated with 6 mg/kg mirvetuximab soravtansine intravenously once every 3 weeks, including one expansion cohort with corticosteroid eye drops administered daily for the first 10 days of each treatment cycle. Results: FRa expression was absent from human corneal tissues. Ocular abnormalities in the rabbit eye appeared phenotypically consistent with off-target effects on the cornea. Forty patients were enrolled in the expansion cohort. Reversible grade 1 or 2 blurred vision and keratopathy occurred in 16 (40%) and 12 (30%) patients, respectively; no grade 3/4 ocular events were observed. Compared with those patients who did not receive primary prophylaxis, corticosteroid eye drop use resulted in fewer dose reductions (5% vs. 15%) and none discontinued due to ocular AEs. Conclusions: Preclinical modeling was predictive of the corneal-related symptoms seen in some patients dosed with mirvetuximab soravtansine. Primary prophylactic use of topical corticosteroid eye drops resulted in a trend toward symptomatic improvement and a reduction in ocular AE-related dose modifications in patients treated with mirvetuximab soravtansine.

<p>Further Understanding of High-Grade Serous Ovarian Carcinogenesis: Potential Therapeutic Targets</p>

“…Prophylactic corticosteroid drops may be effective in reducing eye toxicity. 85 A phase III trial (FORWARD I, NCT02631876) randomized platinum-refractory HGSOC patients with intermediate to high FRα expression who had received up to three lines of therapy between mirvetuximab soravtansine and chemotherapy (either paclitaxel, pegylated liposomal doxorubicin or topotecan). 86 Median PFS was not different in the two groups (4.1 months and 4.4 months).…”

An open-label phase I dose-escalation study of the safety and pharmacokinetics of DMUC4064A in patients with platinum-resistant ovarian cancer

“…The most frequent AEs resulting in a dose modification were blurred vision and peripheral neuropathy. Ocular toxicities have been observed with other ADCs and shown to respond to prophylactic use of topical corticosteroid eye drops [17]. Ocular toxicities observed in this study may be due to anti-tubulin effects and potentially mediated by MUC16 expression in the epithelium of the eye, and were mainly managed with lubricating and moisturizing eye drops.…”

Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody–drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors

“…Ophthalmic AEs were reported in < 10% of patients treated with BMS-986148 in CA008-002, and the majority were low grade, suggesting that targeting mesothelin or using tubulysin as a payload may result in less ophthalmic toxicity than with other ADC molecules. Indeed, these types of events have most often been reported in patients treated with ADCs containing maytansinoid DM4 or monomethyl auristatin-F, with blurred vision and keratopathy observed in 40% and 30% of patients, respectively (40). Treatment with anetumab, a mesothelin-directed ADC under clinical development with a maytansinoid tubulin inhibitor DM4 and hindered disulfide linker (9), has been associated with TRAEs requiring dose reduction in approximately half of patients, including keratitis (21%), blurred vision (11%), and peripheral neuropathy (13%) (41).…”