Corneal Toxicity of ABT-414 in Glioblastoma (GBM): Clinical Manifestations, Ophthalmological Findings and Management

Abstract

Purpose : ABT-414 is an antibody-drug conjugate consisting of a toxin, MMAF (monomethyl auristatin F), linked to an anti-EGFR antibody (ABT-806). Although there is promising antitumor activity of ABT-414 in GBM, it has been associated with corneal toxicity (CT). The pathophysiology of these toxicities is poorly understood. Herein we report the manifestations and management of CTs associated with ABT-414 in GBM.

Methods : M12-356 (NCT01800695) is an open-label, phase 1, 3-arm study: Arm A (ABT-414+radiation (RT)/ temozolomide (TMZ) in newly diagnosed GBM (nGBM)), Arm B (ABT-414+TMZ either in nGBM as adjuvant therapy, or in recurrent GBM (rGBM)) and Arm C (ABT-414 monotherapy in rGBM). Severity of each ocular adverse event (AE) was rated according to NCI CTCAE Version 4.1. The dose-toxicity relationship was analyzed by logistic regression and the onset of CTs was determined by Kaplan-Meier analysis.

Results : As of September 29, 2015, total number of patients reported with one or more ocular treatment-emergent AEs (TEAEs) were 40/45 (89%, Arm A), 42/48 (88%, Arm B) and 59/74 (80%, Arm C). Most common TEAEs (≥25% in at least one arm) for Arms A/B/C respectively, were blurred vision (64%/52%/53%), dry eye (36%/17%/24%), keratitis (33%/25%/20%) and photophobia (33%/38%/24%). Most common Grade (G) 3/4 TEAEs (≥10% in at least one arm) were keratitis (13%/15%/14%) and blurred vision (11%/6%/4%). Overall percent ocular G3/4 TEAEs were 27%/25%/28%. An apparent dose-toxicity relationship was observed in each arm. Median onset times of G2 or higher CTs were comparable among all arms at recommended phase 2 doses, ranging from 49-65 days. Manifestations included microcystic keratopathy, corneal crystals, stromal opacities, limbal stem cell deficiency, punctate epithelial erosion, and filament/corneal abrasions. Management included prophylactic dexamethasone or prednisolone acetate (PA) eye drops, and treatment with bandage contact lenses, punctal plugs, topical preservative-free artificial tears, antibiotics, PA, and/or cyclosporine eye drops. For G3/4 toxicities, ABT-414 was held until toxicity resolved and re-treatment began at a lower dose.

Conclusions : Frequent CTs were observed with ABT-414 treatment in GBM. However, the promising antitumor activity of ABT-414 in GBM warrants further evaluation into strategies to help manage or prevent these toxicities.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.