As antibody-drug conjugates (ADCs) become increasingly common in oncology care and clinical trials, ophthalmologists are more frequently being asked to evaluate and grade associated ocular adverse events. A set of anatomically specific ocular toxicity grading scales, developed by a multicenter interspecialty working group, is gaining attention for its role in improving consistency of assessment and guiding dose modification decisions for experimental ADCs, particularly in settings where existing Common Terminology Criteria for Adverse Events have proven insufficient. The scales aim to clarify terminology, separate objective signs from subjective symptoms, and offer explicit recommendations for dose modification, potentially reducing the risk of premature discontinuation of promising ADC therapies.

The consensus recommendations, which were originally released in June 2023 in response to the I-SPY 2 neoadjuvant breast cancer trial, aimed to address limitations of the previous Common Terminology Criteria for Adverse Events (CTCAE) by separating ocular signs from symptoms, using anatomically specific terminology, incorporating representative clinical photographs, and providing explicit drug dose modification guidance. An overview was recently published in JAMA Ophthalmology. 

Ocular Toxicity With ADC Therapy

Twelve ADC agents have been approved by the US Food and Drug Administration (FDA) in more than 160 clinical trials. Ocular toxicity—most notably corneal pseudomicrocysts—occurs in up to 90% of patients receiving certain ADCs. These corneal changes are associated with blurred vision and eye pain but have been shown to be reversible with dose delay, reduction, or discontinuation. Previous CTCAE limitations—ambiguous terminology, mixing of objective signs with subjective symptoms, lack of standardized clinical photographs, and absence of guidance on experimental drug dose modification—contributed to inconsistent grading and premature discontinuation of ADC therapy in more than 50% of affected patients in the I-SPY 2 trial before the updated scales were released, despite no long-term ocular morbidity being observed.

The consensus group of 23 ophthalmologists and oncologists from 11 US academic centers, along with representatives from the FDA, developed grading scales (grades 0 to 4) for the following domains:

• Eye symptoms (pain, discomfort, tearing, photophobia, blurred vision), which incorporated the Wong-Baker FACES Pain Rating Scale
• Visual acuity, based on change from baseline best-corrected or pinhole-corrected Snellen acuity
• Cornea
• Conjunctiva/sclera, using the validated Efron conjunctival hyperemia scale
• Anterior chamber, adapted from Standardization of Uveitis Nomenclature criteria
• Retina/posterior segment, which incorporated vitreous cell and haze criteria from established uveitis trials

Each grade includes corresponding recommendations for experimental drug continuation, dose delay, dose reduction, or consideration of discontinuation. Corneal pseudomicrocysts were intentionally excluded from corneal grading because they can be difficult to visualize and may be asymptomatic in up to 30% of affected patients.

Surveyed panelists demonstrated high agreement with the new scales, with mean Likert scores ranging from 4.3 to 4.5 out of 5 across individual domains. The mean Likert score was 4.6 when compared directly with CTCAE version 5.0. Since implementation in the I-SPY 2 trial, dose modifications guided by the new grading system have not resulted in reported irreversible ocular toxicity.

Physician Perspectives

Despite their effectiveness in the I-SPY 2 trial, the scales may still be limited in the real world. “I rarely use the ADC AE scales,” ocular oncologist Tim Murray, MD, told Retinal Physician. “I think they are more important when grading for clinical trials.” Dr. Murray’s focus is instead on ophthalmologists’ awareness of possible impacts on the eye from ADC exposure. “Outside of the clinical trial arena,” he continued, “excellent diagnostic focus and documentation of findings are key. Further, in this complex setting, the ophthalmologist must work with the medical oncologist to target treatment approaches for each individual patient. Most importantly, the ophthalmologist must take a good medical history AND a good drug treatment history.”

He also stressed the importance of clinicians understanding new treatment classes with extension of new ADCs and checkpoint inhibitors. “Be aware,” he advised. “We are seeing potentially novel ocular complications. I cannot overemphasize understanding on- and off-target adverse events, and the importance of documentation and communication with medical oncologists. Often, these ocular AEs can be managed conservatively without requiring discontinuation of the treatment regimen. Currently, patients on ADC treatment have often exhausted conservative cancer treatments and these novel treatments may be their only hope to treat their disease and prolong survival.”

“Ophthalmologists who do not routinely see patients on these medications and do not have constant contact with medical oncologists should definitely have this grading scale available when seeing patients on ADC medications,” Basil K. Williams Jr., MD, Medical Director of Ocular Oncology, Associate Residency Program Director, and Associate Professor of Ophthalmology at the Bascom Palmer Eye Institute added in a conversation with RP. “This scale prevents confusion and misinterpretations by having clear assessment guidelines.”

About his experience of using the scales to direct patient management, he said, “They provide an excellent framework for the appropriate response to severity of disease when previous iterations of ocular side effects from other cancer related treatments suggested delaying or stopping medications far too liberally. I see at least a few patients per month on these medications and appreciate the guidance. I sometimes make slight modifications after communication with the medical oncologists, but that is what individualized care is all about.” RP