Eyeworld

FALL 2025 | EYEWORLD | 51 C Contact Chamberlain: chamberw@ohsu.edu Farooq: afarooq@bsd.uchicago.edu Pasricha: Neel.Pasricha@ucsf.edu Relevant disclosures Chamberlain: AbbVie, GlaxoSmithKline Farooq: AbbVie, Ambrx, Amgen, AstraZeneca, Boehringer Ingel- heim, Eisai, GlaxoSmithKline, Mythic Therapeutics, Pfizer, Sanofi, Santen, Skye Bioscience, Vicore Pharma Pasricha: AbbVie, Amgen, AstraZeneca, Sanofi and three have a black box warning from the FDA, which is the highest warning they can is- sue about a drug toxicity. With so many ADCs in clinical trials, Dr. Pasricha said this will likely be a big issue for at least the next 10–20 years. While he said it doesn't seem to be one type of antibody that causes this toxicity, there is research being done into what makes an ADC more likely to cause toxicity. It could be some- thing with charge distribution or hydrophobic- ity impacting how easily it can cross the cell membrane. The general hypothesis of how this is happening is the process of macropinocytosis, which means the cell membrane remodels and "drinks" things non-specifically from the ex- tracellular fluid, he said. This off-target nature makes it a hard problem to fix. Dr. Pasricha has recently been a part of an effort to form a multicenter consensus on grad- ing of these ocular toxicity issues. The idea for this started when he was speaking with Laura Esserman, MD, head of the University of Cali- fornia, San Francisco breast cancer center. She had asked for Dr. Pasricha's help looking at the corneal epithelium in patients in trials for breast cancer drugs. "When I started seeing these patients, one of the first problems I had was they would come to my clinic with ocular toxicities, and the grad- ing scale was difficult for me to understand," he said. "They had confusing terms. I had to grade their dry eye score, their keratitis score, their blurred vision score. I had all of these categories to grade the same underlying problem." This set Dr. Pasricha on the path to making a better grading scale. Dr. Esserman suggested that he consult with ophthalmologists, oncologists, and FDA representatives to tackle the issue. "It wasn't to replace the gold standard, which is the Common Terminology Criteria for Adverse Events (CTCAE), but it was to have a better consensus scale that would make it easier to speak the same language," Dr. Pasricha said. Some of the major advances from this effort were separating out the visual acuity from the objective clinical findings. We didn't include a vision scale in the cornea score, he said. It was a separate visual acuity score and cornea score. "We separated the signs and symptoms, we had representative pictures, and we had recom- mended changes to the oncology drug," he said. Dr. Farooq and Dr. Chamberlain worked with Dr. Pasricha and others in this effort. The CTCAE has historically been used across oncology trials. "This space of targeted cancer drugs and ocular adverse events is growing, and there's some unique findings and con- siderations, so we thought the CTCAE wasn't adequate for facilitating clear communication between ophthalmologists and oncologists." He added that many of these clinical trials and different drugs had their own system and scale. "The idea was to get some minds together who have different perspectives and come up with a grading scale that could be used across different targeted cancer drugs. "Originally, this was thought to be just for ADCs, but once we started getting this panel together, we decided we should make it rele- vant for any experimental oncology drug," Dr. Pasricha said. "For each grade, there's an oncol- ogy drug recommendation." The work done by this group is currently under review with JAMA Ophthalmology. Stopping the drug, reducing, or delaying the dose does help, he said. It's important to provide some guidance on when you should dose delay, dose reduce, or discontinue the drug. However, the guidance can't be so strin- gent that every grade 3 needs to be stopped. "We tried to build things like that into the guidelines, where there's flexibility in the frame- work to account for unique patient clinical scenarios," he said. For most oncologists, when a patient com- plains of eye pain or blurry vision, they'll refer to the eyecare provider, and the same with the eyecare provider—when we see toxicities in the eye, we aren't comfortable saying that they should stop a drug. It is so important to have team communication, he said. We need to carry this throughout the coun- try, Dr. Pasricha said, noting that ADCs are given at infusion centers. It's important to have an eyecare provider as a regional champion about ocular toxicities with these, he said. "I think discussions like this are important because the more people working on this, the faster we'll find better solutions," Dr. Pasricha said. His lab is working on developing eye drops to address this. Right now, there's no known ef- fective therapy except dose interruption. There's a huge need for an effective therapy that will al- low patients to be on the drug without as many side effects or be on a higher dose without the eye problems, he said.

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