TY - JOUR
T1 - Reversible HER2 antibody-drug conjugate–induced ocular toxicity
AU - Sharma, Anushree
AU - Riaz, Kamran M.
AU - Gill, Mohsain S.
AU - Patnaik, Amita
AU - Ulahannan, Susanna V.
AU - Wang, Judy S.
AU - Gombos, Dan S.
AU - Ang, Qiuqing
AU - Cicic, Dragan
AU - Bergonio, Gregory R.
AU - Zhang, Cong
AU - Wirostko, Barbara M.
N1 - Funding Information:
At the time of data collection, A.S. and B.M.W. report personal fees as consultants and medical monitors for Klus Pharma, Inc. D.C. was a Klus Pharma, Inc, study sponsor. G.R.B. was a Klus Pharma, Inc, employee. A.P. reports research funding from Klus Pharma., Inc. S.V.U. reports research funding from Klus Pharma, Inc, and outside submitted work involvement as advisory board member and research funding recipient from other entities. J.S.W. reports research funding from Klus Pharma, Inc, and outside submitted work involvement as a speaker, advisory board member, and research funding recipient from other entities. D.S.G. reports research funding from Klus Pharma, Inc, and outside submitted work involvement as consultant for Seattle Genetics and unpaid consultant for Auro Biosciences and 3 Tophthalmis. No other relevant financial disclosures were declared for all remaining authors.
Publisher Copyright:
© 2021 Canadian Ophthalmological Society
PY - 2022/4
Y1 - 2022/4
N2 - Purpose: To report 3 cases of reversible epitheliopathy induced by A166—a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate (ADC) therapy for resistant HER2 tumours. Methods: Advanced HER2 tumour patients were enrolled in A166 phase I/II clinical trial using Bayesian logistic regression model dose escalation. Key exclusion criteria were ≥grade 2 (G2) corneal pathology, severe organ disease, and other cancer therapy within 4 weeks. Eye exams were performed at baseline, regularly scheduled intervals, and additionally upon A166-induced ocular symptoms. Topical therapy with autologous serum tears (ASTs) was implemented based on visual acuity, symptoms, and slit lamp exam. A166 was withheld if ≥G2 ocular toxicity developed; if status improved to ≤G1, A166 therapy was resumed. Visual acuity, corneal exam, and subjective comfort were recorded. Results: After ≥2 cycles of A166, 6 eyes of 3/23 enrolled patients developed whorl pattern epitheliopathy suggestive of limbal stem cell (LSC) dysfunction requiring cessation of A166 despite positive tumour response. Patients 1 and 3 received 3.6 mg/kg A166 dose, and patient 2 received 3.0 mg/kg. Topical steroids (2/4 eyes) failed to improve epitheliopathy. Adding ASTs improved vision, ocular comfort, and whorl pattern epitheliopathy in 6/6 eyes within 3 weeks. Patient 1 continues to improve on ASTs; patient 2 withdrew from the study; and patient 3 resumed A166 therapy. Conclusion: A166 precipitates LSC dysfunction-like epitheliopathy. Combination therapy including aggressive lubrication, withholding drug, and ASTs help reverse toxicity. Recognizing that ADC-induced epitheliopathy can respond to ocular management may enable cancer patients to continue lifesaving therapy.
AB - Purpose: To report 3 cases of reversible epitheliopathy induced by A166—a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate (ADC) therapy for resistant HER2 tumours. Methods: Advanced HER2 tumour patients were enrolled in A166 phase I/II clinical trial using Bayesian logistic regression model dose escalation. Key exclusion criteria were ≥grade 2 (G2) corneal pathology, severe organ disease, and other cancer therapy within 4 weeks. Eye exams were performed at baseline, regularly scheduled intervals, and additionally upon A166-induced ocular symptoms. Topical therapy with autologous serum tears (ASTs) was implemented based on visual acuity, symptoms, and slit lamp exam. A166 was withheld if ≥G2 ocular toxicity developed; if status improved to ≤G1, A166 therapy was resumed. Visual acuity, corneal exam, and subjective comfort were recorded. Results: After ≥2 cycles of A166, 6 eyes of 3/23 enrolled patients developed whorl pattern epitheliopathy suggestive of limbal stem cell (LSC) dysfunction requiring cessation of A166 despite positive tumour response. Patients 1 and 3 received 3.6 mg/kg A166 dose, and patient 2 received 3.0 mg/kg. Topical steroids (2/4 eyes) failed to improve epitheliopathy. Adding ASTs improved vision, ocular comfort, and whorl pattern epitheliopathy in 6/6 eyes within 3 weeks. Patient 1 continues to improve on ASTs; patient 2 withdrew from the study; and patient 3 resumed A166 therapy. Conclusion: A166 precipitates LSC dysfunction-like epitheliopathy. Combination therapy including aggressive lubrication, withholding drug, and ASTs help reverse toxicity. Recognizing that ADC-induced epitheliopathy can respond to ocular management may enable cancer patients to continue lifesaving therapy.
KW - Bayes Theorem
KW - Clinical Trials, Phase I as Topic
KW - Clinical Trials, Phase II as Topic
KW - Cornea/pathology
KW - Humans
KW - Immunoconjugates/metabolism
KW - Tears/metabolism
KW - Toxic Optic Neuropathy
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UR - http://www.scopus.com/inward/citedby.url?scp=85103058838&partnerID=8YFLogxK
U2 - 10.1016/j.jcjo.2021.02.028
DO - 10.1016/j.jcjo.2021.02.028
M3 - Article
C2 - 33727105
AN - SCOPUS:85103058838
SN - 0008-4182
VL - 57
SP - 118
EP - 126
JO - Canadian Journal of Ophthalmology
JF - Canadian Journal of Ophthalmology
IS - 2
ER -