Ocular Surface Adverse Events and Changes Related to Antibody-Drug Conjugates

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Article initiated by:

Asim V. Farooq, Noah Heilenbach, Shivam Amin, Zhuangjun Si, MD

All contributors:

Asim V. Farooq, Noah Heilenbach, Zhuangjun Si, MD, Vatinee Y. Bunya, MD, MSCE, Brian Lee, MD, Sarah Brown Weissbart, MD, Shivam Amin, Farida Hakim

Assigned editor:

Sarah Brown Weissbart, MD

Review:

Assigned status Up to Date

 by Sarah Brown Weissbart, MD on July 5, 2024.

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Introduction

ADCs are a novel class of drugs used for the treatment of certain cancers resistant to traditional therapies. These drugs consist of a tumor-specific monoclonal antibody (MAB) linked to a cytotoxic payload. The MAB component attaches to its tumor-specific antigen on cancer cells, and the entire ADC is endocytosed. The cytotoxic payload is then cleaved by lysosomal enzymes within cancer cells. This activates a cascade of events resulting in cellular apoptosis. (Figure 1) Ocular surface toxicity is one of the most common adverse events (AE) associated with ADCs.

Two proposed mechanisms for ADC-mediated damage are on-target versus off-target toxicity. On-target toxicity may occur via receptor-mediated endocytosis in ocular surface cells that express the target antigen for a specific ADC. Off-target toxicity may occur through Fc-receptor mediated entry, macropinocytosis of the ADC (also known as “cell drinking”), or bystander toxicity due to premature cleavage of the linker in the bloodstream and liberation of the cytoxic payload. Passive diffusion of the cytotoxic payload through the permeable cell membrane could also cause off-target toxicity. (Figure 2)

Figure 1: Structure of Belantamab mafodotin, an antibody-drug conjugate (ADC) used for treatment-resistant multiple myeloma. An IgG1 monoclonal antibody (mAb) targeting B-cell maturation antigen (BCMA) expressed on multiple myeloma cells is linked to the cytoxic payload monomethyl auristatin F (MMAF), a microtuble disrupter. Modified figure reprinted with permission from Farooq, A.V., Degli Esposti, S., Popat, R. et al. Corneal Epithelial Findings in Patients with Multiple Myeloma Treated with Antibody–Drug Conjugate Belantamab Mafodotin in the Pivotal, Randomized, DREAMM-2 Study. Ophthalmol Ther (2020). https://doi.org/10.1007/s40123-020-00280-8. Copyright Springer Nature.

Figure 3: Slit lamp photographs of microcyst-like epithelial changes (MECs), sometimes seen best with retroillumination. Arrowheads point towards MECs. Reprinted with permission from Farooq, A.V., Degli Esposti, S., Popat, R. et al. Corneal Epithelial Findings in Patients with Multiple Myeloma Treated with Antibody–Drug Conjugate Belantamab Mafodotin in the Pivotal, Randomized, DREAMM-2 Study. Ophthalmol Ther (2020). https://doi.org/10.1007/s40123-020-00280-8. Copyright Springer Nature.

Figure 4: In vivo confocal microscopy (IVCM) images of a patient with MECs (a-d). MECs were most prominent wing cells (b) and basal cells (c) compared to superficial epithelial cells (d). Reprinted with permission from Farooq, A.V., Degli Esposti, S., Popat, R. et al. Corneal Epithelial Findings in Patients with Multiple Myeloma Treated with Antibody–Drug Conjugate Belantamab Mafodotin in the Pivotal, Randomized, DREAMM-2 Study. Ophthalmol Ther (2020). https://doi.org/10.1007/s40123-020-00280-8. Copyright Springer Nature.

Currently Approved Medications

Table 1. FDA approved ADCs as of April 2023

Drug	Trade name	target	General Indication
Gemtuzumab[AF1] ozogamicin	Mylotarg	CD33	CD33+ relapsed or refractory AML
Brentuximab vedotin	Adcetris	CD30	Lymphoma
Adotrastuzumab emtansine	Kadcyla	HER2	HER2+ breast cancer
Inotuzumab ozogamicin	Besponsa	CD22	Relapsed or refractory B-ALL
Polatuzumab vedotin-piiq	Polivy	CD79b	Relapsed or refractory DLBCL
Enfortumab vedotin-ejfv	Padcev	Nectin4	Urothelial cancer
Famtrastuzumab deruxtecan-nxki	Enhertu	HER2	HER2+ breast cancer; HER2+ gastric or gastroesophageal junction adenocarcinoma
Sacituzumab govitecan-hziy	Trodelvy	TROP2	Metastatic triple-negative breast cancer; urothelial cancer
Loncastuximab tesirine-lpvl	Zynlonta	CD19	Large B-cell lymphoma
Belantamab mafodotin	Blenrep	BCMA	Relapsed or refractory multiple myeloma. *Withdrawn in 2022 because confirmatory phase 3 trial did not meet primary efficacy endpoint
Tisotumab vedotin-tftv	Tivdak	TF	Recurrent or metastatic cervical cancer
Mirvetuximab soravtansine	Elahere	FR-alpha	Platinum-resistant ovarian cancer
Moxetumomab Pasudotox	Lumoxiti	CD-22	Hairy cell leukemia
Disitamab Vedotin	Aidixi	HER2	Gastric carcinoma, Urothelial carcinoma

Reported Adverse Events

Pseudomicrocysts

a. Disease entity: ADCs lead to the formation of corneal epithelial inclusions that begin near the limbus and extend centrally as drug dosage and duration of therapy increase (Figure 3). These changes occur bilaterally and are termed “pseudomicrocysts” or “microcyst-like” because they are not felt to represent true microcysts. In vivo confocal microscopy (IVCM) has demonstrated the presence of round, hyperreflective intracellular structures most prominent in the basal layer of the epithelium with relative sparing of the superficial epithelium. (Figure 4) It is unclear what these hyperreflective structures are, but one leading hypothesis is that they represent the internalization or phagocytosis of ADCs by corneal epithelial cells. No material is seen within the stroma or endothelium. These corneal changes have been reported with the use of multiple ADCs including belantamab mafodotin and mirvetuximab soravtansine.

b. Presentation: Patients may complain of symptoms such as irritation, blurred vision, tearing, and photophobia, although often patients are asymptomatic. Diminished visual acuity and subjective feelings of blurred vision may be correlated with more centrally located pseudomicrocysts.  Both hyperopic and myopic shifts have been observed and correlated to their location.

c. Risk Factors: Patients with a history of dry eye prior to starting a course of ADCs may be predisposed to the development of pseudomicrocysts.

d. Histopathology: In a recent case series by Kreps et al. of two patients who developed pseudomicrocysts from an ADC used to treat glioblastoma multiforme, corneal scrapings from the two patients were examined microscopically. Histology revealed epithelial cells with a vacuolated, granular appearance at various stages of apoptosis. Basal epithelial cells and engulfed apoptotic cells stained positive for IgG on immunohistochemistry. These findings suggest that there is a mechanism by which ADCs are internalized by corneal epithelial cells and exert their cytotoxic effects.

e. Pathophysiology: Corneal epithelial cells theoretically undergo ADC-induced cell death, facilitating further (peripheral) pseudomicrocysts that migrate centrally as new epithelial cells are produced. It is unclear whether ADCs enter the cornea through the vascularized limbus or through the tear film, although their pattern of migration suggests the former. In the cases of belantamab mafodotin and mirvetuximab soravtansine, the target is not expressed in corneal or conjunctival epithelial cells. Thus, an off-target pathway is suspected.

Conjunctivitis

Figure 5. Clinical image demonstrating sub-epithelial fibrosis on the palpebral conjunctival surface in a patient treated with Tivdak.

Conjunctivitis typically presents with bilateral bulbar and/or palpebral hyperemia and complaints of burning, itching, tearing. Patients may have concurrent blepharitis or eyelid irritation.  Conjunctivitis is a reported side effect of tisotumab. Subepithelial fibrosis has also been observed. (Figure 5)

Limbal stem cell dysfunction

Patients may present with worsening of dry eye symptoms. Staining with fluorescein demonstrates a whorl pattern staining typical of limbal stem cell dysfunction.

Superior limbic keratoconjuctivitis

Superior limbic keratoconjunctivitis has been observed with the use of mirvetuximab soravtansine.

Figure 2: Potential mechanisms of ADC-mediated damage to corneal epithelial cells. Reprinted with permission from de Goeij BE, Lambert JM. New developments for antibody-drug conjugate-based therapeutic approaches. Curr Opin Immunol. 2016;40:14–23.https://doi.org/10.1016/j.coi.2016.02.008

Management

As with most patients who are on anti-cancer therapies with potential ocular side effects, the mainstays of management revolve around routine follow-up, dose modification, and supportive care. Avoidance of contact lens wear may also reduce surface toxicity. Punctal plugs may increase the concentration or exposure of the ocular surface to these medications as well.

Routine eye exams

Patients should get baseline examinations prior to initiation of medications with potential ophthalmic toxicity and be monitored every cycle or sooner with increased symptoms. The KVA scale can be used to grade the level of keratopathy.

Medical therapy

Patients, particularly those with dry eye upon baseline examination, are advised to start preservative-free artificial tears four times a day in both eyes. Prophylactic artificial tears should be prescribed for patients starting enfortumab and tisotumab. Prophylactic topical corticosteroids have been used with mixed results. They have been suggested to be effective in mitigating ocular adverse events associated with the ADCs depatuxizumab mafodotin (ABT-414) and vorsetuzumab mafodotin (SGN-75), both of which contain the cytoxic payload monomethyl auristatin F (MMAF). Steroid prophylaxis with 1% prednisolone 4-6 times daily during the first 10 days of a treatment cycle of mirvetuximab soravtansine appeared to reduce the incidence of keratopathy. Long-term steroid treatment should be used with caution due to risk of secondary infection as well as usual risk of ocular hypertension, glaucoma and cataract. Other treatments that are typically used for patients with severe ocular surface disease such as vitamin A ointment and oral doxycycline (20 mg PO BID) may also be beneficial.

Dose Modification

In the presence of ocular surface adverse events, it may be advisable to delay treatment and reduce the dose of the medication. For example, dose delays and reductions have been shown to reduce MECs in the DREAMM-2 study which was a phase 2 study of the ADC belantamab mafodotin used for multiple myeloma.Table 2 shows the recommended dose modifications for belantamab mafodotin based on the keratopathy visual acuity (KVA) scale, which is composed of corneal findings and change in BCVA. Corneal changes from this and other MMAF-containing ADCs were reversible with treatment cessation, often showing resolution from a few weeks to several months. Similar dose modifications have also been recommended for patients undergoing treatment with mirvetuximab soravtansine, as outlined by Hendershot et al. Dose modifications and delays are also recommended for tisotumab in presence of keratitis or conjunctivitis more severe than Grade 1. Discontinuation is recommended in the setting of severe keratitis with ulceration, Grade 3 or 4 conjunctivitis, and any sign of corneal or conjunctival scarring or symblepharon.

Table 2: Grading scale for MECs with recommendations for treatment modification developed by Farooq, et al. for the ADC Belantamab mafodotin used for multiple myeloma. Reprinted with permission from Farooq, A.V., Degli Esposti, S., Popat, R. et al. Corneal Epithelial Findings in Patients with Multiple Myeloma Treated with Antibody–Drug Conjugate Belantamab Mafodotin in the Pivotal, Randomized, DREAMM-2 Study. Ophthalmol Ther (2020). https://doi.org/10.1007/s40123-020-00280-8. Copyright Springer Nature.

Prognosis

Awareness of ocular surface adverse events, with appropriate monitoring and treatment is key for patient outcomes. The symptoms and ocular findings typically resolve with cessation of the medication with good visual recovery. Pseudomicrocysts largely resolve with discontinuation or tapering of the offending agent as pseudomicrocyst-containing cells are replaced with healthy, regenerated cornea epithelium.  Resolution of symptoms and regeneration of the corneal epithelium can vary from weeks to months. Conjunctivitis, such as that caused by agents like tisotumab, can result in long term conjunctival scarring.