New grading scale improves eye safety monitoring in cancer drug trials

A working group of ophthalmologists and oncologists have reached a consensus on a new scale to grade drug-related ocular adverse events in oncology trials. This new scale was created to address ambiguous terms in version 5 of the Common Terminology Criteria for Adverse Events (CTCAE) and to provide recommendations for drug dose modification, according to the authors of a new paper published in JAMA Ophthalmology.

“These new ocular AE grading scales have facilitated safe and effective evaluation of eye toxicity from ADCs in the curable breast cancer setting. This concerted multidisciplinary effort is a model for addressing emerging toxicities associated with new therapies, providing clarity and consistent grading for AE reporting,” wrote the authors, who were led by Neel D. Pasricha, M.D., assistant professor of ophthalmology at the University of California, San Francisco.

Version 5 of the National Cancer Institute’s CTCAE scale included ocular adverse events such as blurred vision, eye pain, and keratitis, and it is considered the gold standard for the assessment of toxicities in oncology clinical trials. Version 6 of the CTCAE was published in July 2025.

During the I-SPY 2 trial, investigators found that the CTCAE scale included mixed signs and symptoms, ambiguous terms, and no dose modification recommendations. I-SPY 2 is an adaptive clinical trial testing experimental drugs used before surgery for patients with high-risk early-stage breast cancer.

Oncologists were concerned about patient vision loss, and they were uncomfortable with the inconsistent classification of ocular adverse events. For example, the scale did not include a consensus on what constituted grade 2 keratitis, and complete resolution of keratitis was not clearly defined. Keratitis is an inflammation of the cornea. Oncologists were also unsure how to modify the dosing of the cancer therapy when patients experienced adverse events.

In February 2023, the FDA Center of Excellence in Regulatory Science and Innovation (CERSI) formed a working group of oncologists and academic ophthalmologists from 11 academic centers in the United States to determine and develop new grading of ocular adverse events in oncology clinical trials.

The working group developed six experimental oncology drug–related ocular adverse event grading scales for oncologists to use during antibody-drug conjugate clinical trials. These include visual acuity, eye symptoms, cornea, conjunctiva/sclera, anterior chamber, and retina/posterior segment. These new grading scales were implemented into the I-SPY 2 trial protocol on June 22, 2023.

The new scale contains clear anatomical adverse event terms, separate signs and symptoms, representative photographs, and dose modification recommendations. The dose recommendations are provided to prevent vision loss or damage to the eyes.

“This new scale is a huge improvement over what we had before, and has enabled us to test new antibody drug conjugates, despite evidence of some ocular toxicity. As well, it has enabled our collective team to identify the exact toxicity and come up with potential solutions which will be game changing for some of these new agents,” said corresponding author Laura J. Esserman, M.D., MBA, professor of surgery and Radiology at the University of California, San Francisco (UCSF) and the director of the UCSF Breast Care Center.

The authors said the dose modifications proposed by the new ocular AE grading scales in the I-SPY 2 trial have not caused any irreversible eye toxicity. "We are studying alternative methods to screen for ocular AEs in patients, such as portable screening with eye imaging in the oncology clinic. Additionally, we are exploring the underlying mechanisms of ADC-induced corneal toxicity and the development of novel preventive therapies,” the authors wrote.

The authors note that although the new grade scale was specifically designed to be used for the investigation of antibody drug conjugates in the I-SPY 2 trial, it may be applicable for other experimental oncology drug–related ocular adverse events.