Ocular Surface Toxicity of Antibody–Drug Conjugates: Pathogenesis, Diagnosis, Grading, and Treatment of Ocular Adverse Effects

Abstract

Purpose:

The American Society of Cornea and Refractive Surgery Cornea Committee convened to create a brief review of the literature and expert experience of antibody–drug conjugates (ADCs) and their impact on ocular surface health.

Methods:

Peer-reviewed publications from 2003 to 2025 were evaluated. The information along with authors clinical experience was used to create a white paper on the current aspects ADC therapy that is relevant to the ocular surface health.

Results:

There are currently 14 Food and Drug Administration–approved ADCs. By most recent estimates in the literature, there are more than 200 ADCs currently in development, and a significant proportion of them are associated with keratopathy that has unique ocular surface manifestations. Features of ADC-induced keratopathy include corneal pseudocysts, superficial punctate keratitis, refractive shifts, and conjunctival hyperemia. More severe adverse events such as conjunctival hemorrhage, conjunctival scarring, and corneal ulcers are rare. These findings correlate with change in visual acuity and visual quality. Eye care providers need guidance to recognize, understand, and communicate critical features of vision health with referring oncologists.

Conclusions:

Given the anticipated surge in oncology patients on ADCs, there is a need for dissemination of information on ocular surface concerns. This review covers key aspects ADC toxicity mechanisms and pathological features on the ocular surface health including strategies to diagnose, grade, and treat disease. It also provides expectations on the eye care provider's role in communication with referring oncologists.

Antibody–drug conjugates (ADCs) are a rapidly evolving class of targeted cancer therapies designed to deliver potent cytotoxic agents directly to tumor cells. Since the approval of the first ADC in 2000, the field has expanded substantially, 14 agents now FDA approved (Table 1) and many more in development across a spectrum of malignancies.^1,2 Despite their clinical success, ADCs have been associated with off-target effects, including a growing recognition of ocular surface toxicity. As these agents are increasingly incorporated into systemic cancer regimens, understanding their mechanisms, molecular components, and potential for ocular surface injury has become essential for both oncologists and ophthalmologists.

TABLE 1.

FDA-Approved ADCs

ADC Name (yr FDA Approval)	Target	IgG Subclass	Payload	Indication	Ocular Toxicity
Gemtuzumab ozogamicin (Mylotarg) (2000)	CD33	IgG4	Calicheamicin	AML	None reported
Brentuximab vedotin (Adcetris) (2011)	CD30	IgG1	MMAE (auristatin)	Hodgkin lymphoma, ALCL	Rare: dry eye and blurred vision
Trastuzumab emtansine (Kadcyla) (2013)	HER2	IgG1	DM1 (maytansinoid)	HER2+ breast cancer	Dry eye, keratopathy
Inotuzumab ozogamicin (Besponsa) (2017)	CD22	IgG4	Calicheamicin	ALL	None reported
Polatuzumab vedotin (Polivy) (2019)	CD79b	IgG1	MMAE (auristatin)	DLBCL	Rare: blurred vision
Enfortumab vedotin (Padcev) (2019)	Nectin-4	IgG1	MMAE (auristatin)	Urothelial carcinoma	SPK, dry eye, blurred vision
Trastuzumab deruxtecan (Enhertu) (2019)	HER2	IgG1	DXd (topoisomerase I inhibitor)	HER2+ breast, gastric, lung cancers	Corneal epithelial microcysts, SPK
Sacituzumab govitecan (Trodelvy) (2020)	Trop-2	IgG1κ	SN-38 (topoisomerase I inhibitor)	TNBC, urothelial cancer	Keratopathy, dry eye, blurred vision, photophobia
Loncastuximab tesirine (Zynlonta) (2021)	CD19	IgG1	PBD dimer	DLBCL	None reported
Tisotumab vedotin (Tivdak) (2021)	Tissue factor	IgG1	MMAE (auristatin)	Cervical cancer	Conjunctivitis, dry eye, keratopathy, blepharitis, corneal ulceration
Mirvetuximab soravtansine (Elahere) (2022)	Folate receptor-α	IgG1	DM4 (maytansinoid)	Ovarian cancer	Vision impairment, keratopathy, dry eye, cataract, photophobia, eye pain
Telisotuzumab vedotin (Emrelis) (2025)	c-Met	IgG1κ	MMAE (auristatin)	Nonsquamous nonsmall cell lung cancer	Blurred vision, keratitis, dry eye, photophobia
Datopotamab deruxtecan (Datroway) (2025)	TROP2	IgG1	DXd (topoisomerase I inhibitor)	Nonsmall cell lung cancer	Dry eye, keratitis, tearing, blurred vision
Belantamab mafodotin (Blenrep) (2025)*	BCMA	Afucosylated IgG1	MMAF (auristatin F)	Multiple myeloma	SPK, microcysts, vision loss
Moxetumomab pasudotox (Lumoxiti) (2018)†	CD22	Recombinant murine (Fv)-immunotoxin	PE38 (Pseudomonas exotoxin A)	Hairy cell leukemia	Blurred vision, dry eye, conjunctivitis, discharge

^*Belantamab was received FDA approval in 2025 to be used in combination with bortezomib and dexamethasone.

^†Moxetumomab was taken off the market because of low clinical uptake and commercial reasons.

ALCL, Anaplastic Large Cell Lymphoma; AML, Acute Myeloid Leukemia; BCMA, B-Cell Maturation Antigen; DLBCL, Diffuse Large B Cell Lymphoma; PBD, Pyrrolobenzodiazepine; TNBC, Triple Negative Breast Cancer.

MECHANISM OF ACTION OF ADCs

ADCs combine the specificity of monoclonal antibodies with the lethality of small-molecule drugs known as cytotoxic payloads. The payloads are connected to the ADC via chemically engineered tethers or linkers that ensure stability in circulation and efficient intracellular drug release. Each of the 3 components play distinct roles in killing tumor cells via recognition, therapeutic potency, and pharmacokinetics and mediating off target toxicity (Fig. 1).³

FIGURE 1.

Schematic structure of an antibody–drug conjugate.

Antibody Component

The monoclonal antibody binds to antigens that are overexpressed on malignant cells. Many ADCs use humanized or fully human IgG1 antibodies selected because of their favorable pharmacokinetics and ability to engage immune effector functions such as antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Target antigens ideally have limited or no expression on normal tissue, rapid internalization upon antibody binding, and sustained surface expression. Examples include HER2 (trastuzumab), CD30 (brentuximab target), CD33 (gemtuzumab), and Trop-2 (sacituzumab).

Linker

The linker bridges the antibody and payload and can determine the ADC's activation pharmacokinetics. Linkers are classified as cleavable or noncleavable. Cleavable linkers exploit tumor-specific micro-environments achieving cleavage via acidic pH, protease activity, or reductive conditions. Noncleavable linkers require complete lysosomal degradation of the antibody backbone to liberate the drug. Linker design has to take into account risks for premature payload release, which can increase toxicity to healthy tissues.⁴

Cytotoxic Payload and Cellular Targets

The payload is the cytotoxic element responsible for inducing cell death. Because of the limited drug-to-antibody ratio, payloads are ultra-potent, with IC₅₀ values in the low nanomolar to picomolar range. The most common payload mechanisms include microtubule disruption and DNA damage, each with distinct cellular and toxicological consequences. Other payloads made of macromolecules such as Pseudotox (PE-38) can disrupt protein synthesis. Table 2 lists payloads in Food and Drug Administration (FDA)-approved ADCs and their targets and mechanisms of action. Emerging classes of payloads such as BCL-xL inhibitors and RNA polymerase inhibitors are under evaluation. Mechanisms of action, membrane permeability, and bystander toxicity all influence ocular adverse effects.⁵

TABLE 2.

ADC Payloads: Classification, Mechanism, and Cellular Targets

Category	Specific Names	Cellular Target	Mechanism of Action	Membrane Permeability
Microtubule inhibitors	MMAE, MMAF (auristatins) DM1, DM4 (maytansinoids)	Tubulin	Inhibit tubulin polymerization, disrupting mitosis and causing cell cycle arrest	MMAE/DM1: permeable; MMAF/DM4: poorly permeable
DNA damaging agents	Calicheamicin	DNA	Induces double-stranded DNA breaks via radical formation	Permeable
DNA alkylators	Duocarmycin	DNA minor groove	Alkylates adenine in A-T rich sequences, leading to DNA damage	Permeable
DNA cross-linkers	PBD dimer	DNA	Forms covalent cross-links in DNA without helical distortion	Highly permeable
Topoisomerase inhibitors	Camptothecin, SN-38, DXd (exatecan derivative)	Topoisomerase I	Stabilize DNA-topoisomerase I complex, causing replication fork collapse and cell death	Moderately permeable
Protein synthesis inhibitors	PE-38 (Pseudomonas exotoxin A)	Elongation factor-2 (EF-2)	Inactivates EF-2, halting protein synthesis and leading to apoptosis	Not permeable (requires receptor-mediated entry)

PBD, Pyrrolobenzodiazepine.

CORNEAL ADVERSE EVENTS (AEs) ASSOCIATED WITH ADCs

Corneal toxicity is increasingly reported across multiple ADCs (Table 1) and appears to reflect a combination of direct epithelial injury, inflammatory cytokine release, and collateral bystander effects. Epithelial microcysts are frequently observed. These are actually pseudocysts that may reflect dead or degenerating cells in various layers of the cornea endothelium and can also appear as waves of white dots migrating from the peripheral to central cornea. Although much of the literature refers to them as microcysts, confocal microscopy and histopathology reports suggest that they are not cystic, but likely are clusters of dead or dying cells with intracytoplasmic inclusions.^6,7 Although the literature refers to them in different terminologies, “corneal epithelial pseudocysts and corneal epithelial microcysts essentially refer to the same exam finding; we propose that the preferred terminology moving forward should be corneal epithelial pseudocysts.” In addition, ocular surface toxicity can manifest as superficial punctate keratitis (SPK), conjunctival injection and inflammation, refractive shifts, limbal stem cell dysfunction or deficiency, and ultimately corneal epithelial defects and stromal ulceration. These will be covered in detail below.

Pathogenesis of Corneal AEs in Patients Using ADCs

Once the ADC binds to the targeted cell, it is internalized and the payload is released to cause damage and destruction to the cancer cell. Nonspecific uptake of ADCs by various tissues can lead to toxicity of otherwise healthy organs. The growing number of ADCs available for the treatment of various cancers has revealed that the eye is one of the most frequently affected organs, regarding adverse effects.⁸ The eye may be exquisitely sensitive to toxicity because of its robust blood supply, presence of many rapidly dividing cells including the corneal epithelium, and some ocular surface epithelial cell receptors that overlap with the cancer cell antibody receptors. Thus, many of the ADC AEs affect the cornea. There are several possible mechanisms for toxicity, which can be classified into 2 types: on-target effects and off-target effects.^8–10

Mechanism of Corneal Toxicity

On-target effects occur with antibody-mediated delivery. The specific tumor marker recognized by an ADC can be expressed on healthy cells as well (Fig. 2A). These interactions can lead to introduction of payload into nontargeted cells. The HER-2 receptor, which is a target for breast cancer drugs trastuzumab emtansine and trastuzumab duocarmazine, is overexpressed in some neoplasms but is also found in normal corneal epithelial cells. Dry eye and conjunctivitis are the most reported AEs.^8,9

FIGURE 2.

On-target and off-target mechanisms of antibody–drug conjugates.

Off-target effects occur with the delivery of an unconjugated payload, which can occur through several possible mechanisms. One mechanism is an unstable linker in the ADC causing premature release of the cytotoxic payload from the monoclonal antibody. A linker can end up being unstable in vivo because of several factors such as degradative proteases, other enzymes in blood, or off-target tissues and variations in pH.^9,11 This leads to the payload exerting its action in the wrong tissues, causing cell damage. Another mechanism of off-target effects can occur as-a-result of the intracellular metabolism by which the linker is separated from the payload. The ionized intermediate metabolites may become trapped within the cytoplasm, causing cell damage.^8,12 Yet another potential mechanism is the diffusion of the payload into the extracellular space: either through an intact cell membrane or because of loss of cellular integrity after cell death. Once in the extracellular space, the payload can enter other cells by a variety of methods, including simple diffusion, transporter-mediated uptake, or nonspecific endocytosis.^8,11

Endocytosis has proven to be an important off-target means of entry into healthy cells. There are 2 types of endocytosis: pinocytosis, which is a receptor-independent and nonspecific means of internalizing extracellular fluid, and phagocytosis, a receptor-dependent and nonspecific means of internalizing larger particulate matter. The most important mechanism of endocytosis is macropinocytosis, which involves endocytic vacuoles in the size range of 0.2–10 μm. Macropinocytosis is thought to be a significant mechanism of corneal epithelial toxicity in belantamab, used to treat relapsed or refractory multiple myeloma. Certain nonspecific receptors (which are expressed on corneal epithelial cells), such as Fc gamma receptors, neonatal Fc receptor, and C-type lectin receptors, can mediate phagocytosis by interacting with the Fc region of the monoclonal antibody (Fig. 2B).^8,11

Although there are several corneal AEs reported with ADCs, some ADCs have rare or no ocular side effects despite targets being expressed in ocular tissues. An example is the lymphoma drug, brentuximab vedotin, which recognizes CD30, which is expressed in the conjunctiva.¹³ Further research is needed to elucidate why no corneal AEs would occur despite the presence of target receptors in ocular surface cells, which could depend on pharmacokinetics and tissue localization unique to ADCs and their subcomponents.

Routes of ADCs Access to the Cornea

ADCs can enter the cornea via 3 possible routes of access: limbal vasculature, tear film, and aqueous. The limbal vasculature access likely explains why some corneal AEs start in the corneal periphery and progress centrally. The highest concentration of ADC would be at limbal cells. But payloads may release with varying kinetics in these cells as they differentiate and migrate toward the central cornea. Peripheral versus central corneal pathology could depend on varying payload kinetics within the cells. The presence of belantamab mafodotin in tears has been demonstrated in a rabbit study; however, this ADC is suspected of being internalized into corneal epithelial cells via macropinocytosis, leading to cellular toxicity.^8,12 The aqueous may not be a route that leads to toxicity, as ocular effects are largely isolated to the ocular surface, and the endothelium is spared while anterior stroma is occasionally involved.¹⁴

DIAGNOSIS

Corneal AEs

Corneal AEs have been reported with several of the available ADCs (Table 1). Unfortunately, the clinical methods used to assess patients affected by corneal AEs are rarely reported in the literature, including slit-lamp utilization and/or consultation with corneal specialists,⁹ and there are often few patients reported per study.⁸ The identification of some rarer and more severe corneal AEs also occur merely with case reports and anecdotal communications.

Corneal Pseudocysts

Corneal epithelial pseudocysts are a common finding caused by several ADCs. This was the most commonly reported AE (∼70%) for belantamab mafodotin.¹⁵ Microtubule-disrupting monomethyl auristatin-F, the payload associated with this ADC, is most commonly associated with corneal toxicity and can reach the cornea via the limbal vasculature and possibly via tears. Off-target metabolism of the linker to monomethyl auristatin-F leads to intracellular accumulation of ionized cytotoxic metabolites within corneal epithelial cells, in turn leading to apoptosis. Cellular toxicity manifests as corneal epithelial pseudocysts (Fig. 3), which more commonly occur after multiple doses of belantamab mafodotin, especially in higher doses. The sick cells then migrate from the basal layer of the epithelium more anteriorly until they are extruded onto the corneal surface, leading to SPK (Fig. 4). Some of the pseudocysts start forming in the corneal periphery, closest to the limbal vasculature, and encroach toward the visual axis, thus affecting visual acuity.¹² Although most patients with central corneal changes were symptomatic, some were asymptomatic. Patients with a history of dry eyes before belantamab mafodotin treatment were at higher risk of developing blurred vision.⁸ Mirvetuximab soravtansine contains the DM4 payload (soravtansine), which inhibits tubulin polymerization and disrupts microtubule assembly, arresting the cell in the G₂/M and inducing apoptosis. In patients receiving this ADC, the prevalence of blurred vision was 23% to 50% and keratopathy (including keratitis, corneal epithelial pseudocysts, and limbal stem cell deficiency) was 20% to 26%.¹⁶ A case series of 5 patients on mirvetuximab reported that all 5 patients had bilateral corneal pseudocysts mainly in the corneal periphery, which later migrated toward the center. All 5 patients reported blurred vision, and some reported pain, tearing, photophobia, and foreign-body sensation.¹⁷ Belantamab mafodotin was removed from the US market in November 2022 because of failure of a phase III confirmatory trial (DREAMM-3) in meeting the primary end point of progression-free survival.¹⁸ In October 2025, the FDA approved belantamab mafodotin in combination with bortezomib and dexamethasone based on efficacy data from the DREAMM-7 trial. Approval came with a Boxed Warning for the risk of ocular toxicity to the corneal epithelium. Availability of the drug is only through the manufacturer's Risk Evaluation and Mitigation Strategy.

FIGURE 3.

Mirvetuximab soravtansine (A), tisotumab vedotin (B), and belantamab mafodotin (C) associated corneal epithelial pseudocysts seen with retro-illumination and light scatter during slit-lamp examination.

FIGURE 4.

Diffuse SPK associated with belantamab mafodotin.

SPK, also known as punctate epithelial erosions, is a finding seen universally with most ADCs with corneal AEs. This finding may be because of both on-target and off-target effects (Fig. 4). Trastuzumab emtansine and trastuzumab duocarmazine both bind the HER-2 receptor, which is also expressed on corneal epithelial cells.^8,9 When trastuzumab duocarmazine interacts with HER-2, it is internalized within lysosomes, where the linker is destroyed, and the active toxin is released through alkylation of cellular DNA, which then induces apoptosis. Dry eyes were reported in 31% of patients, and there were also reports of keratitis. Trastuzumab emtansine only had 4.5% of patients reporting blurred vision, with reports of a few cases of mild keratitis.⁸ Enfortumab vedotin (used to treat bladder and urinary tract cancers) binds to Nectin-4, which is then internalized by endocytosis. The payload is monomethyl auristatin-E, a microtubule disruptor, leading to apoptosis. Dry eye symptoms were reported in 36% of patients, with blurred vision in 14% (thought to be related to dry eyes).^19,20 Tisotumab vedotin (used to treat cervical cancer) also releases its payload monomethyl auristatin-E via interaction with tissue factor in an on-target fashion. The incidence of mild-to-moderate ocular AEs has been reported as 54% (with none severe); 23% of all patients experienced dry eyes and 11% had SPK.^8,19 There was a low rate (1.4%) of conjunctival ulceration in the FDA trial.²¹

Changes in refractive error have also been reported in patients receiving ADCs. The same case series mentioned previously of 5 patients with corneal AEs on mirvetuximab showed that against-the-rule hyperopic astigmatic shift was observed in 3 eyes of 2 patients. A larger case series of 29 patients receiving different ADCs found that patients with peripheral corneal epithelial pseudocysts were associated with hyperopic shifts compared with baseline, and patients with paracentral/central pseudocysts were associated with myopic shifts. The range of refractive shift was between +3.75 and −4.75 diopters. The shifts showed correlation with flattening or steepening of keratometry values, respectively.²²

Other AEs

Published literature on limbal stem cell deficiency, epithelial defects, and stromal ulceration is scant. There is mention of limbal stem cell deficiency with mirvetuximab, but it is lumped into the same category as keratitis and corneal epithelial pseudocysts with no further explanation.¹⁶ Moreover, the term “keratitis” is also used very generally, which is usually (but not always) intended to mean SPK, and there is little published data on the incidence of epithelial defects and ulceration. Only 1 patient (out of 95 total) was reported to have either an epithelial defect or stromal ulceration in the DREAMM-2 study for belantamab mafodotin.⁶ Ulcerative keratitis was seen in 2% to 11% of the clinical trials for tisotumab vedotin.¹⁰ The same mechanisms of epithelial toxicity for epithelial pseudocysts and SPK may be at play for epithelial defects and ulceration on a more severe and confluent scale. In addition, there can be conjunctival manifestations including hyperemia and subconjunctival hemorrhage. More standardization in identifying and grading ocular AEs across multiple ADCs and particularly preapproval clinical trials would be helpful to identify commonalities and differences in ADC ocular AEs.

MODALITIES FOR DIAGNOSIS

Slit-Lamp Examination (SLE)

Slit-lamp biomicroscopy remains the cornerstone of anterior segment evaluation in patients undergoing ADC therapy. Experience in recognizing the subtle epithelial findings is important. Corneal epithelial pseudocysts present as fine, translucent, intraepithelial lesions typically observed bilaterally. These lesions often are first found in the peripheral cornea and may migrate toward the mid-peripheral and central cornea as severity progresses (Fig. 4).^10,23–27 Pseudocysts are best visualized using retro-illumination or indirect illumination techniques.⁶

SPK or PEEs are optimally identified with fluorescein staining and cobalt blue illumination. These epithelial changes may resemble those seen in dry eye disease, underscoring the importance of correlating clinical findings with the patient's treatment history. Some patients may also exhibit a whorl or flame-like pattern of epithelial staining, similar to that seen in limbal stem cell dysfunction or deficiency.^6,23,28

In more severe cases, SLE can find, localize, and grade corneal ulceration and stromal thinning. These AEs pose a significant risk of secondary infection and corneal perforation, necessitating prompt and aggressive intervention and strong consideration of ADC cessation. Conjunctival findings noted on SLE may include bulbar conjunctival injection (Fig. 5), mucous discharge, and occasionally subepithelial fibrosis. These can mimic infectious or allergic conjunctivitis. On lid eversion, fibrotic changes of the tarsal conjunctiva may be evident, highlighting the necessity of a comprehensive anterior segment examination. One report described pseudomembranous conjunctivitis and meibomitis after 4 treatment cycles of tisotumab vedotin.²⁹

FIGURE 5.

Severe conjunctival injection and subconjunctival hemorrhage associated with tisotumab vedotin.

Topography

Corneal topography may reveal distinctive changes that correlate with the distribution of epithelial changes and pseudocysts (Fig. 6). Peripheral corneal epithelial pseudocysts can result in localized peripheral corneal steepening with compensatory central flattening, producing an oblate topographic pattern similar to that seen after myopic excimer laser ablation. This may induce a hyperopic shift. In contrast, central corneal epithelial pseudocysts tend to produce central steepening, associated with a myopic shift.^22,30 Topography likely is irregular in most cases and may correlate with loss of best spectacle-corrected visual acuity.

FIGURE 6.

Corneal tomography showing shifting areas of corneal steepening from baseline before therapy (A) to the central cornea (B) 6 weeks after ADC initiation.

Anterior Segment Optical Coherence Tomography (OCT)

Anterior segment OCT (AS-OCT), particularly with epithelial thickness mapping, has emerged as a noninvasive modality for assessing epithelial architecture of patients being treated with ADCs. Most reports have focused on patients receiving belantamab mafodotin, where the pseudocysts appear as discrete, hyperreflective intraepithelial lesions on AS-OCT (Fig. 7). These findings differentiate them from true cysts, which appear hyporeflective.^25–27 Corneal epithelial maps have shown an increase in corneal epithelial thickness shortly after belantamab mafodotin infusion. These areas of thickening correspond to the area of pseudocysts and imaging may aid in both diagnosis and monitoring. Mencucci et al²⁵ reported that there was a subsequent decrease of corneal epithelial thickness during subsequent infusions, which could reflect long-term limbal stem cell dysfunction after repeated exposure to some payloads.

FIGURE 7.

Anterior segment OCT showing hyperreflective epithelial layer corresponding to corneal pseudocysts after ADC treatment.

Confocal Microscopy

In vivo confocal microscopy (IVCM) provides high-resolution, cellular-level imaging of the cornea and is particularly valuable for assessing ADC-related toxicity. Multiple studies have described hyperreflective intracellular inclusions within the corneal epithelium, mostly in patients treated with belantamab mafodotin.^6,23–25 These inclusions are typically observed as small, round, hyperreflective spots in the basal epithelium (Fig. 8), which enlarge as they ascend to the wing cell layer. The superficial epithelial layer may contain cyst-like, hyporeflective structures with hyperreflective borders and a core of variable reflectivity.^23,24 In addition, IVCM has revealed disruption of the subbasal nerve plexus, indicating a neurotoxic effect of ADCs on corneal innervation. Aschauer et al²³ demonstrated nerve fiber fragmentation as early as 3 weeks after the initial belantamab mafodotin infusion. Eventually, complete loss of the subbasal nerve plexus was observed in 7 out of 7 patients at the final follow-up. These changes are not limited to belantamab mafodotin. Depatuxizumab mafodotin, an ADC used in the treatment of glioblastoma, has also been associated with the formation of hyperreflective intraepithelial round inclusions in the basal epithelium. Subbasal nerve plexus fragmentation was evident by week 2, with progressive nerve fiber loss noted by week 4. Restoration of the subbasal nerve plexus was observed 8 weeks after treatment discontinuation.³¹

FIGURE 8.

Confocal microscopy image of corneal basal cell layers of patient on belantamab mafodotin (Courtesy of Asim Farooq, MD).

Anterior Segment Infrared Reflectance (AS-IR)

AS-IR imaging has emerged as a useful adjunct for documenting and monitoring ADC-related keratopathy. Epithelial pseudocysts appear on AS-IR as variably sized, hyporeflective circles, which may coalesce into larger patches in advanced stages.^17,32 Unlike the small field of view imaged with IVCM and AS-OCT, AS-IR allows rapid imaging of the entire corneal surface in 1 image, facilitating more efficient longitudinal monitoring of the pseudocysts. Notably, 1 study demonstrated the presence of AS-IR hyporeflective lesions up to 6 weeks before they were detectable on SLE, suggesting a potential role in early detection.³¹

CATEGORIZATION/GRADING SCHEMES FOR KERATOPATHY

To best standardize corneal findings in these unique classes of medications, grading schemes have been developed some of which are specific to study design while other more practical for clinical applications. Two common schemes to characterize corneal findings includes the Keratopathy and Visual Acuity (KVA) scale and the Common Terminology Criteria for Adverse Events (CTCAE) v6.0 scale.

KVA Scale

The KVA scale was developed to document the severity of belantamab mafodotin–induced ocular toxicity and to make treatment adjustments.⁶ This developed as a more practical grading method after the familiar Oxford Scale was used in the DREAMM-1 first-in-human trial.³³ In addition, its development was based on the concerns that the standard CTCAE scale for AES would miss ocular toxicity signs that do not correlate with symptoms. The DREAMM-2 study outlined the objective findings of slit-lamp examination and best-corrected visual acuity (BCVA) independent of patient-reported symptoms.⁶ Corneal findings identified on either BCVA scale or KVA scale guide management with the worst eye determining the grading. In grade 1, there is mild superficial keratopathy and/or decline of BCVA up to 1 line. In grade 2, there is moderate superficial keratopathy and/or decline of BCVA of 2 to 3 lines. In grade 3, there is severe superficial keratopathy and/or decline of BCVA of more than 3 lines. In grade 4, there is a corneal epithelial defect including corneal ulceration and/or BCVA worse than 20/200. If the patient has grade 1 changes, belantamab treatment is continued. If the patient has grade 2 to 3 changes, belantamab treatment is withheld until the patient returns to grade 1, at which point treatment is continued at a reduced dose. Grade 4 requires consideration of treatment cessation.

CTCAE v6.0 Scale

The CTCAE v6.0 scale, published by the National Cancer Institute, is used to grade AEs based on symptoms and effects on daily functioning.³⁴ This well-validated scale uses a scale from 1 to 4 to describe ocular AEs (and a scale from 1 to 5 to describe systemic AEs). Specific guidelines on relevant anterior segment AEs are outlined in Table 3. The full CTCAE v6.0 ocular AE scale is extensive and covers a wide range of anterior segment and posterior segment AEs, which are outside the scope of this report. Grade 1 AEs are those that are asymptomatic. Grade 2 AEs are symptomatic findings with BCVA 20/40 or better. Grade 3 AEs are symptomatic findings with BCVA worse than 20/40 but better than 20/200. Grade 4 AEs are symptomatic findings with BCVA 20/200 or worse.

TABLE 3.

Excerpts From the CTCAE v6.0 Scale for Grading Ocular AEs From Medical Treatments or Procedures.

Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Blurred vision
Intervention not indicated	Symptomatic; moderate decrease in visual acuity (best-corrected visual acuity 20/40 and better or ≤3 lines decreased from known baseline); limiting instrumental ADL or mild/moderate impact on age-appropriate normal daily activity (pediatric)	Symptomatic with marked decrease in visual acuity (best-corrected visual acuity worse than 20/40 or >3 lines decreased from known baseline, up to 20/200); limiting self-care ADL or severe impact on age-appropriate normal daily activity (pediatric)	Best-corrected visual acuity of 20/200 or worse in the affected eye	—
Definition: A disorder characterized by visual perception of unclear or fuzzy images
Navigational note: Consider: eye disorders: uveitis
Cataract
Asymptomatic; clinical or diagnostic observations only; intervention not indicated	Symptomatic; moderate decrease in visual acuity (best-corrected visual acuity 20/40 and better or ≤3 lines decreased from known baseline); glare symptoms affecting instrumental ADL or mild/moderate impact on age-appropriate normal daily activity (pediatric)	Symptomatic with marked decrease in visual acuity (best-corrected visual acuity worse than 20/40 or >3 lines decreased from known baseline, up to 20/200); limiting self-care ADL or severe impact on age-appropriate normal daily activity (pediatric)	Best-corrected visual acuity of 20/200 or worse in the affected eye	—
Definition: A disorder characterized by partial or complete opacity of the crystalline lens of 1 or both eyes. This results in a decrease in visual acuity and eventual blindness if untreated
Navigation note: —
Corneal ulcer
—	—	Corneal ulcer without perforation in the affected eye	Perforation in the affected eye	—
Definition: A disorder characterized by an area of epithelial tissue loss on the surface of the cornea. It is associated with inflammatory cells in the cornea and anterior chamber
Navigational note: —
Dry eye
Clinical or diagnostic observations only; symptoms relieved by lubricants	Symptomatic; moderate decrease in visual acuity (best-corrected visual acuity 20/40 and better or ≤3 lines decreased from known baseline)	Symptomatic with marked decrease in visual acuity (best-corrected visual acuity worse than 20/40 or >3 lines decreased from known baseline, up to 20/200); limiting self-care ADL or severe impact on age-appropriate normal daily activity (pediatric)	—	—
Definition: A disorder characterized by dryness of the cornea and conjunctiva
Navigational note: If corneal ulcer is present, grade under eye disorders: corneal ulcer. If related to syndromes not present in CTCAE (e.g., Sjögren syndrome), report as other, specify in the most representative SOC.
Keratitis
Asymptomatic; clinical or diagnostic observations only; intervention not indicated	Symptomatic; moderate decrease in visual acuity (best-corrected visual acuity 20/40 and better or ≤3 lines decreased from known baseline)	Symptomatic with marked decrease in visual acuity (best-corrected visual acuity worse than 20/40 or >3 lines decreased from known baseline, up to 20/200); corneal ulcer; limiting self-care ADL or severe impact on age-appropriate normal daily activity (pediatric)	Perforation; best-corrected visual acuity of 20/200 or worse in the affected eye	—
Definition: A disorder characterized by inflammation to the cornea of the eye
Navigational note: Consider eye disorders: corneal ulcer
Vision decreased
—	Moderate decrease in visual acuity (best-corrected visual acuity 20/40 and better or ≤3 lines decreased from known baseline)	Marked decrease in visual acuity (best-corrected visual acuity worse than 20/40 or >3 lines decreased from known baseline, up to 20/200)	Best-corrected visual acuity of 20/200 or worse in the affected eye	—
Definition: A disorder characterized by a decrease in visual acuity
Navigational note: If etiology is known, use a more specific CTCAE term. Consider: eye disorders: uveitis

Note that the full CTCAE v6.0 ocular AE scale is more extensive and covers extraocular, anterior segment, and posterior segment AEs.

ADL, Activities of Daily Living; SOC, System Organ Class.

However, concerns arose that the CTCAE v6.0 scale underestimated the severity of ocular toxicity, especially for the cornea, in which signs typically arise before symptoms. Other concerns include lack of precision and challenges with reporting.³⁵ Nevertheless, the CTCAE v6.0 scale continues to be important for documentation of AEs with emphasis on collaboration between clinical trial sponsors, oncologists, and ophthalmologists.

Numerous scales and the mixing of ocular signs and symptoms in the CTCAE system is a continuous source of confusion and difficulty in standardizing the specific ocular surface and visual effects of ADCs. Toward this dilemma, Pasricha et al³⁶ in 2025 assembled a collaborative multicenter interspecialty working group consisting of academic ophthalmology and oncology providers FDA to form a consensus on new oncology drug-related ocular AE grading scales. Moving forward, this tool should be considered as a monitoring device across emerging drug trials to standardize ocular toxicity ratings.

MANAGEMENT

The treatment of corneal toxicity related to ADCs is focused on managing symptoms and supportive care. Thankfully, despite a diverse range of AEs related to ADCs, nearly all resolve with cessation of the offending medication and supportive treatment.⁹ In the setting of a multidisciplinary treatment approach, communication between the ophthalmologist and the oncology team is critical. Depending on the severity of ocular AEs, the oncologist may choose to 1) continue ADC treatment with the standard dose, 2) continue ADC treatment with a reduced dose, 3) hold the next dose, or 4) completely stop therapy with the current ADC medication. In addition, cataloging the adverse effects of ADCs continues to evolve. Monitoring for early problems and intervention can help to reduce risk of permanent corneal damage related to these medications.

Given the variation and high frequency of ocular surface signs and symptoms among patients on ADCs, and the timing of their onset, there is no consensus on the frequency and timing of ocular exams that are necessary. Various ocular toxicology screening and remediation protocols have been used in ADC clinical trials that included baseline ocular exams with follow-up exams after defined numbers of infusions, and add-on exams for emergent symptoms. Implementation of these schedules in post approval real-world settings risk overwhelming already busy ophthalmology practices. Numerous emerging agents (>200 ADCs currently in clinical trials) could create referral backlogs and communication challenges between oncologists and eye care providers. In addition, awareness and comfort among eye care providers to monitor an enlarging new pool of patients, especially in geographic areas with provider shortages, will likely add to access challenges. One possible solution would be to train a dedicated force of eye care providers (including comprehensive or general ophthalmologists, optometrists, and physician associates) to recognize abnormal ocular surface changes and to standardly grade and report findings to oncologists. Referral to corneal subspecialists might then only be necessary for more severe emergent events.

Several prophylactic measures can be taken prior ADC treatment in the hopes of reducing the risk of corneal toxicity. It is possible that bandage contact lenses and punctal plugs may adversely elevate ocular surface ADC concentration, although more investigation is required to understand if this is a real concern. Prophylactic use of preservative-free artificial tears is common, as nearly all ADCs are associated with SPK.³⁷ Topical corticosteroids treatment before ADC treatment and/or before documented corneal toxicity has been shown to potentially decrease rate of AEs. ADC patients on tisotumab vedotin, depatuxizumab mafodotin, vorsetuzumab mafodotin, and mirvetuximab soravtansine, but not belantamab mafodotin, may benefit.^38–40 Additional prophylactic measures aimed at minimizing corneal drug absorption include the use of cold compresses over the eyes during ADC infusion, and the use of topical vasoconstrictors, such as phenylephrine and brimonidine, which may reduce peak concentrations of ADCs at the limbus during infusion.⁴¹

If ocular toxicity develops, reducing or stopping the use of the offending ADC will generally lead to resolution of corneal epithelial pseudocysts, SPK, and refractive changes. Providers should be aware that resolution of pseudocysts in the MMAF-containing ADCs typically takes several weeks to months.^6,42–44 In addition to changes in the administration of the ADC, which might include either reduced dosing or reduced frequency of dosing, supportive care measures include ongoing use of preservative-free artificial tears and topical corticosteroids. Topical steroids may also be beneficial in reducing down-stream effects of conjunctival toxicity including scarring and symblephara. However, steroids have the known side effects of ocular hypertension and cataracts. Cataracts are also more likely to arise in certain cancer patient populations because of age and exposure to multiple chemotherapeutic agents before ADCs.

SPK is common to all ADCs likely from both on-target and off-target effects inducing premature apoptosis and necrosis of epithelial cells. There are several potential therapies used in the dry eye literature that may play a role in ADC keratopathy.⁴⁵ Serum tears contain growth factors such as epidermal growth factor and fibronectin, which promote epithelial cell proliferation and maturation. Because serum tears are usually autologous, there are likely advantages to performing a large serum draw before initiation of ADC therapy to avoid introducing ADC onto the ocular surface from the drops. Alternatively, pooled heterologous tears from screened healthy donors may be a better source for ongoing therapy. It is unclear if the concentration of nonspecific IgG in serum tears could compete with ADC for uptake in the ocular surface environment reducing the toxic effect similar to the action of intravenous immunoglobulin therapy. Similarly, use of topical vitamin A ointment to promote faster epithelial cell growth, differentiation, and migration may serve to minimize keratopathy side effects. Topical insulin drops may also promote epithelial proliferation, migration, and antiapoptotic activity. Approved ocular surface therapies that target inflammatory pathways and aqueous production may play a role in alleviating symptoms associated with ADC-induced keratopathy. These include topical calcineurin inhibitors such as cyclosporine A and tacrolimus, intracellular adhesion molecule blockers such as lifitegrast, tear production secretagogues such as the nasal spray varenicline, acoltremon drops, and oral agents such as pilocarpine and cevimeline. Investigation into the safety and efficacy of all these therapies demands investigation as our literature search found little evidence of use and efficacy in ADC patients.

In addition, the use of bandage contact lenses, scleral lenses, and amniotic membranes may play a protective or therapeutic role in more severe forms of keratopathy associated with epithelial breakdown.

DISCUSSION

There are currently well over 200 ADCs in clinical trials. Ocular toxicity including keratopathy is associated with multiple ADCs and those conjugated to auristatins and maytansinoids (eg belantamab mafodotin, depatuxizumab mafodotin, tisotumab vedotin, telisotuzumab vedotin, mirvetuximab soravtansine) may have the higher rates of keratopathy. A recent review of ADCs suggests shifts in usage of various payloads, which may alter the frequency and manifestations of ocular surface toxicity.⁴⁶ Given the relative increase of this class of targeted cancer therapeutics and its current track record of ocular AEs, ophthalmologists and particularly cornea specialists need to understand current risks of approved ADCs and emerging risks from ADCs in trials.

In addition, oncologists need to understand the symptoms associated with patients' eyes and visual health and how to balance these concerns against alteration or cessation of therapy if AEs are severe. In many disease categories, ADCs may be a last-line therapy, and the patients may have limited life expectancy. It is up to the ophthalmologist to communicate with the oncologist on the trajectory of eye health while undergoing treatment with ADCs. Eye care providers are not required to make decisions about dose holds, dose reductions, or cessation of ADC therapy, but they should be able to communicate with oncologists about the potential effects of ocular AEs on patients' quality of life. Interestingly, a recent report based on a large aggregated health record database suggested that patients with higher grade ocular surface toxicity may have better long-term survival suggesting a higher motivation to maintain ADC therapy despite ocular challenges.⁴⁷

Eye care providers must be sensitive to the balance between promoting patients' eye health and the critical priority of maximally treating their cancer. There is a component of medical ethics and medical humanities involved in weighing quality of life versus survival.

There is an expected increase in the number of patients participating in ADC clinical trials, which will all likely have varying ocular AEs profiles, reporting protocols, and algorithms for managing and mitigating these AEs. Given the increasing number of ADC patients expected in the coming decades, and the frequency of visits required, it will be beneficial to have eye care providers specifically trained and dedicated to monitoring and managing ocular AEs from ADCs.