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Associate Professor of Ophthalmology
Vice Chair of Academic Affairs
Director of Medical Student Education
Department of Ophthalmology and Visual Science
University of Chicago Medical Center
Asim V. Farooq, MD, has disclosed that he has received consulting fees from Five Prime Therapeutics/Amgen and GlaxoSmithKline.
Associate Professor of Ophthalmology
Montefiore Medical Center/Albert Einstein College of Medicine
Director, Cornea and Refractive Surgery
Montefiore Medical Center
Bronx, New York
Joann Kang, MD, has no relevant conflicts of interest to report.
Antibody–drug conjugates (ADCs) represent a relatively new class of targeted chemotherapeutic agents for patients with cancer. ADCs comprise a monoclonal antibody that is tethered to a cytotoxic agent (also known as a “payload” or a “warhead”) by a chemical linker that is stable in the circulation but releases the cytotoxic agent in the target cell. ADCs are designed to deliver potent cytotoxic agents to targeted tumor cells while minimizing toxicity to normal tissue.
Globally, more than 600 ADC clinical trials have been conducted or are underway, and based on their efficacy and overall adverse event profile, these drugs have the potential to cause a huge paradigm shift in cancer treatment. There are already several ADCs that have been approved by the FDA for various types of cancers and have been added as an effective treatment strategy in clinical practice.
Although many of the approved ADCs are tolerable and associated with fewer adverse events (AEs) than conventional chemotherapy, as with any cancer therapy, ADCs are associated with specific AEs, and some of these ADCs have reported ocular toxicity. These include belantamab mafodotin for multiple myeloma, tisotumab vedotin for cervical cancer, enfortumab vedotin for urothelial cancer, and trastuzumab deruxtecan for HER2‑positive breast cancer. Ocular AEs associated with these agents include vision loss, corneal ulcers, blurred vision, dry eye, and microcyst-like epithelial changes (MECs). In this commentary, we review the mechanism of ADC ocular toxicity, AE grading, and monitoring and management strategies.
Corneal Changes and Changes in Visual Acuity With ADC Treatment
Ocular changes associated with some ADCs, including belantamab mafodotin and tisotumab vedotin, have distinct appearances that can be seen during ophthalmic examinations. With a slit lamp exam, MECs appear as tiny dots within the corneal epithelium. These lesions start in the periphery of the cornea and can migrate to the paracentral and central cornea over time and with subsequent ADC infusions. However, in some patients and with some ADCs, the central cornea is spared and there’s a ridge of epithelium beyond which the MECs don’t progress, and the reason for that is not yet known. There have also been reports of limbal stem cell dysfunction with ADC treatment, and when the cornea is viewed with green fluorescein there is a notable whorl-like pattern. These changes appear to be reversible with treatment cessation. However, the long‑term outcomes are currently unknown as ADCs have not been used in clinical practice for that long.
Corneal changes can affect visual acuity and quality of vision in 2 ways. First, epithelial changes can occur within the visual axis, blocking or leading to scatter of light, and second, there can be minor changes in the curvature of the cornea and can change the ability of the cornea to focus light onto the retina. Ocular toxicity can also cause dry eye, blurry vision, or ocular discomfort. These corneal changes may affect a patient’s ability to see clearly, and in some cases, corneal changes may lead to treatment discontinuation, particularly if they are not identified and managed promptly.
Managing Ocular AEs Associated With Belantamab Mafodotin
Ocular AEs associated with belantamab mafodotin are graded based on the severity of keratopathy and changes in visual acuity.
Grade 1 keratopathy is mild, superficial, and nonconfluent and MECs are predominantly in the periphery. With grade 1 keratopathy, there can be a decline of baseline best corrected visual acuity by one line on the visual acuity scale. For grade 1 mild keratopathy, we recommend that a patient continue treatment at the current dose.
We consider moderate keratopathy grade 2, and it is associated with a decline in visual acuity by 2‑3 lines, but the visual acuity is not worse than 20/200. With grade 2 keratopathy, MECs are located in the periphery and paracentral region but not in the central cornea. We consider the density to be semiconfluent, and there can also be an associated subepithelial haze. For patients with grade 2 keratopathy, we recommend holding treatment until improvement to grade 1 and then resuming treatment at the same dose. In the DREAMM‑2 trial, approximately 77% of patients who had grade 2 or higher keratopathy recovered from the first event at the time of data cut-off, and the median time to resolution was 86.5 days. So, most patients do eventually recover.
With grade 3 keratopathy, there is a decline of visual acuity by 3 or more lines on the chart, but not worse than 20/200 and we consider this to be a severe ocular toxicity. Diffuse MECs can be found in the central corneal and are confluent. A central subepithelial haze may also be present. For patients with grade 3 keratopathy, we recommend holding treatment until improvement to grade 1 and then resuming treatment at a reduced dose. In the DREAMM‑2 trial, 4 patients had grade 3/4 keratopathy, and 84% recovered or were recovering from the keratopathy at data cut-off.
Finally, with grade 4 keratopathy, there is a corneal epithelial defect (inclusive of a corneal ulcer) and/or visual acuity worse than 20/200. We manage these cases as clinically indicated by the treating ophthalmologist. For patients with grade 4 keratopathy, consider treatment discontinuation. Together, the ophthalmologist and oncologist should do an individual benefit–risk assessment of continuing treatment at a reduced dose when the patient has improved back to grade 1 or better.
Managing Ocular AEs Associated With Tisotumab Vedotin
Grading and management recommendations for ocular toxicity are similar for tisotumab vedotin. Ocular toxicities with tisotumab vedotin include keratitis, conjunctivitis, dry eye, and blurred vision. For superficial punctate keratitis and grade 1 conjunctivitis, therapy with tisotumab vedotin can be continued with close monitoring. For confluent superficial keratitis, hold tisotumab vedotin until resolution of this toxicity and then resume therapy at a lower dose or discontinue for any recurrence. For grade 2 conjunctivitis, hold tisotumab vedotin until resolution and then resume at the same dose for the first recurrence, resume at a lower dose for the second recurrence, or discontinue if there is a third recurrence. For grade 3/4 conjunctivitis or any ulcerative keratitis, corneal perforation, corneal/conjunctival scarring, or symblepharon, permanently discontinue tisotumab vedotin.
Monitoring and Mitigating Ocular Toxicity With ADCs
Ocular monitoring for patients receiving belantamab mafodotin and tisotumab vedotin requires a tremendous amount of coordination because we need to treat these patients for their cancer while also monitoring them from an ophthalmology standpoint. This requires close collaboration and a good working relationship with the whole team, including the hematologist/oncologist, the ophthalmologist, and the pharmacist. We’re in constant communication with each other to ensure that our patients are being treated and having good and safe visual outcomes. Other conditions that can affect ocular toxicity include a history of dry eye and a history of baseline keratopathy. It’s important to monitor patients with these conditions carefully because they can have increased risk as well as earlier onset of ocular symptoms.
Patients receiving belantamab mafodotin should be monitored closely for ocular changes. Eye exams should be performed at baseline and every 3 weeks (prior to each dose) or as clinically indicated. These exams should be performed even during dose delays, regardless of whether the delay is due to a corneal event or a nonocular event.
There are several ways to help mitigate ocular toxicity associated with belantamab mafodotin. Prophylactic ocular lubrication with preservative-free artificial tears is important. As soon as patients come to see us and are being evaluated to start belantamab mafodotin, we start them on preservative‑free artificial tears. We recommend using the artificial tears 4 times per day, beginning with the first dose and continuing until approximately 30 days after the end of their therapy. If patients have baseline dry eye, the treating ophthalmologist can consider and recommend additional supportive therapies and that includes increased frequency of eye drops, ointments, use of punctal plugs, and in some cases, even a bandage contact lens. Eye cooling masks are being evaluated for use at the start of each drug infusion to reduce the diffusion of belantamab mafodotin into the cornea and, therefore, minimize ocular concentration. However, at this point, it is unclear whether cooling masks are helpful. So, this is used at the discretion of the prescriber or in keeping with institutional practices.
Monitoring and management recommendations are similar for tisotumab vedotin. An eye examination should be performed at baseline, prior to each dose, as clinically indicated. In this case, the dose modifications are based on the presence and severity of keratitis and conjunctivitis. For mitigating ocular toxicity with tisotumab vedotin, corticosteroid eye drops and vasoconstrictor eye drops are indicated immediately prior to infusion and cooling eye pads should also be used during infusion. Patients should also be instructed to continue using corticosteroid eye drops for 72 hours after each infusion and using lubricating eye drops for the duration of therapy and for 30 days after stopping treatment with tisotumab vedotin.
It is important to counsel patients to report visual changes and let them know the clinical implications of potential corneal toxicity. It can be difficult for patients who are undergoing treatment for cancer to also have frequent eye exams. Understanding the potential corneal toxicity helps with adherence to the eye exam requirement and helps patients understand that they need to let their treating oncologist or ophthalmologist know if they have any change in their symptoms.
A few sample questions that you can ask your patients are:
Often patients are not using the preservative-free drops frequently. So, it is important to always check with them about adherence. We emphasize at each visit the need for artificial tears and then if the patient’s keratopathy progresses, we recommend additional therapies as clinically indicated.
We also advise our patients to avoid the use of contact lenses during the duration of therapy and to instead wear glasses. They should also use caution when driving or operating machinery.
ADCs are a new class of chemotherapeutic agents and they represent a paradigm shift in how we are treating our patients with some types of cancer. With the use of ADCs, corneal disease has emerged in which microcyst-like changes occur in the epithelium and should be discussed with patients and their care team before beginning therapy with these ADCs. Hopefully, as ADCs continue to be developed, we can learn to optimize their design to minimize these associated toxicities. Until then, we are learning to better manage these toxicities through prophylaxis measures and ongoing patient monitoring and counseling.
To learn more about optimizing the care of patients with ADC-associated ocular toxicity, download this online resource that you can share with your colleagues and watch this on-demand webinar from a live symposium at the American Academy of Ophthalmology’s annual meeting in 2021.
What challenges do you experience with managing ocular toxicities in your patients receiving ADCs? Answer the polling question and join the conversation in the discussion box below.