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POTENTIAL MECHANISM FOR OCULAR ADVERSE EVENTS OBSERVED WITH TISOTUMAB VEDOTIN

Autores: Vergote, I.; Kim, S.; Ursell, P.; Pignata, S.; González Martín, Antonio; Randall, L.; Melichar, B.; Madsen, K.; Mahner, S.; Lorusso, D.; Henry, S.; Gaba, L.; Salcedo, T.; Neff-Laford, H.; Harris, J.; Jiang, J.; Soumaoro, I.; Jain, S.; Monk, B.; Coleman, R. L.
Título de la revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
ISSN: 1048-891X
Volumen: 32
Número: SUPPL 3
Páginas: A74 - A75
Fecha de publicación: 2022
Resumen:
Objectives Tisotumab vedotin (TV), a tissue factor (TF)-directed antibody-drug conjugate (ADC) with a monomethyl auristatin E payload, received accelerated FDA approval for treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. TV-associated ocular adverse events (OAEs) present as symptomatic ocular surface inflammations, dissimilar to microcystic keratopathies reported for other ADCs. We hypothesize TF expression in the eye may be linked to TV-associated OAEs. Methods In vitro human tissue cross-reactivity (TCR) and repeat-dose cynomolgus monkey toxicity studies were conducted. TV was evaluated for efficacy and safety in the pivotal innovaTV 204/GOG-3023/ENGOT-cx6 trial; patients performed mandatory eye care to mitigate OAE risk. Results TCR results indicate TV binds to cryosections of human ocular tissues, including conjunctival epithelium (n=3 donors per tissue). Ocular findings from cynomolgus monkeys receiving TV Q3W for 5 doses (n=5M/5F per dose level) included partially closed eyes and reddened eyes and/or conjunctiva. Binding or inhibiting TF with unconjugated anti-TF antibody in cynomolgus monkeys did not lead to similar ocular findings. In innovaTV 204, 54% of patients exhibited OAEs (1.4-month median onset, IQR 0.7¿2.0), mostly Grade 1¿2 in severity. Common events included conjunctivitis, dry eye, and keratitis. Four patients experienced visual acuity changes; 3 resolved at last follow-up. Conclusions Preclinical data suggest an ocular surface-expressed TF-dependent phenomenon and provide potential mechanistic rationale which may partly contribute to the inflammatory and symptomatic nature of clinically observed TV-associated OAEs. Clinical trial experience suggests adherence to required eye care and appropriate dose modifications reduce risk and severity of OAEs.
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