Pathogenesis and treatment of ocular surface diseases associated with antibody-drug conjugates: a scoping review

Introduction

Background

Cancer is the second leading cause of death worldwide, with an estimated 611,720 deaths occurring in the United States alone in 2024 (1). Treatment previously centered around traditional chemotherapies, which target rapidly-dividing cells. However, this can lead to destruction of normal tissues with high turnover rates (2). In contrast, antibody-drug conjugates (ADCs) are chemotherapeutic agents designed to bind receptors on malignant cells and provide a limited systemic effect profile. With the first approval by the United States Food and Drug Administration (FDA) in 2000, ADCs represent a new and growing approach to treating cancer (3).

ADCs are composed of an antibody, most commonly IgG, and a cytotoxic drug called a payload joined together by a linker protein. The antibody binds to an overexpressed antigen on the malignant cell surface and is endocytosed. Once in the cytoplasm, the linker is cleaved, releasing the payload (4). The toxicity profile of each ADC is due in part to the mechanism of action of the payload, which can prevent mitoses or induce apoptosis (5). Alternatively, the payload can inhibit DNA replication through competitive binding in the minor groove or inhibition of tubulin polymerization within the mitotic spindle (5).

Another component of the toxicity profile of each ADC is the mechanism of action. Direct toxicity occurs when the selective receptor target on the cancer cell is also expressed in the eye. This allows for delivery of the cytotoxic payload directly into the ocular tissues (6). Alternatively, bystander or off-target effect occurs when the cytotoxic payload is taken up from the interstitial space or adjacent tissues, leading to ocular toxicity (7).

Rationale and knowledge gap

Although ADCs have demonstrated high clinical efficacy, several of these drugs have ocular side effects that need to be recognized by the treating physician. Studies have shown that the most common ocular surface diseases (OSDs) include conjunctivitis, corneal pseudomicrocysts, blurred vision, dry eye syndrome, and rarely ulcerative keratitis or symblepharon (6). These side effects are reported in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), which is a standardized system that uses a grading scale to indicate the level of severity of each adverse event experienced by patients undergoing cancer therapy. Grade 1 is associated with mild symptoms (no intervention indicated), grade 2 involves moderate symptoms (minimal intervention indicated), grade 3 is associated with severe but not immediately life-threatening symptoms (often requires hospitalization), grade 4 involves life-threatening consequences (immediate intervention is indicated) and grade 5 involves death related to the adverse event (8). Since ADCs target different receptors, there is significant variability in the incidence rates of OSDs. For example, rates of OSDs in patients taking belantamab mafodotin are over 80% while rates in patients taking polatuzumab vedotin are less than 1%. As such, a widely accepted treatment regimen for both mitigation or treatment has not been established. In addition to ocular therapies, delay or cessation of ADC infusions may be necessary with the development of OSDs (9).

Objective

Given expanding use criteria and that additional ADCs are in development, we review the pathophysiology of ADC-related OSDs, incidence of ADC-related OSD, and current treatment strategies. We present this article in accordance with the PRISMA-ScR reporting checklist (available at https://aes.amegroups.com/article/view/10.21037/aes-25-45/rc).

Methods

A scoping literature search was conducted across several databases and platforms (PubMed, Cochrane, and ScienceDirect) from January 1, 2000, through May 31, 2025 for all FDA approved ADCs. Due to the broad nature of our research question and the systematic search methods utilized to answer this question, a scoping review was selected and performed. Two individuals independently performed the database screening and literature report extraction and adhered to the review protocol listed in the Supplementary materials section, which was established prior to the data retrieval process. Disagreements were resolved through group discussion, ensuring that consensus was met by all authors before proceeding. Search terms included: “antibody-drug conjugate”, “enfortumab vedotin”, “Padcev”, “dry eye”, “keratitis”, “trastuzumab deruxtecan”, “Enhertu”, “Trodelvy”, “sacituzumab govitecan”, “belantamab mafodotin”, “Blenrep”, “loncastuximab tesirine”, “Zynlonta”, “telisotuzumab vedotin”, “Emrelis”, “Tivdak”, “tisotumab vedotin”, “mirvetuximab soravtansine”, “Elahere”, “ocular surface disease”, “cornea”, “photophobia”, “conjunctival injection”, “Kadcyla”, “trastuzumab emtansine”, “Adcetris”, “brentuximab vedotin”, “Besponsa”, “inotuzumab ozogamicin”, “Lumoxiti”, “moxetumomab pasudotox”, “Polivy”, “polatuzumab vedotin-piiq”, “Mylotarg”, “gemtuzumab ozogamicin”, “Datroway”, and “datopotamab deruxtecan”. Boolean operators (AND, OR) were applied to refine the search strategy. Inclusion criteria encompassed peer-reviewed articles reporting ocular adverse effects in patients treated with ADCs. Exclusion criteria included non-peer-reviewed articles, studies not involving OSDs, non-English literature, editorials, letters, systematic reviews, and those lacking specific data on ocular outcomes. Patient characteristics were generally excluded from selected articles, although few studies reportedly consisted of participants ranging from 25–80 years old, and many studies included multinational data. The PRISMA-ScR guidelines were adhered to throughout the review process. Review protocol can be accessed in Appendix 1.

Results

The search query yielded 350 records with 137 duplicate citations. The remaining 213 records were screened by title and abstract. A total of 177 were included for full text review, of which 95 were excluded due to a lack of focus on ADCs and OSDs, 5 were excluded for lacking peer review, and 32 were excluded for not meeting inclusion criteria. A total of 45 articles for inclusion (Figure 1 and Table 1).

Figure 1 Search methods summarized in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) diagram.

In this section, we will discuss the mechanism of action and the associated OSDs for each ADC that have been reported in the literature.

Loncastuximab tesirine

Eight papers referenced OSDs associated with longcastuximab tesirine use, of which three met criteria to be included in this paper. Loncastuximab tesirine-lpyl, also known as Zynlonta, is an ADC targeting CD19 and is approved for treating relapsed or refractory diffuse large B-cell lymphoma (40). Although CD19 is absent on ocular tissues off-target delivery of the pyrrolobenzodiazepine (PBD) payload may result in non-specific cytotoxicity or immune-mediated epithelial inflammation (41). The LOTIS-2 trial, a multicenter, single-arm, phase II study of 145 patients with relapsed/refractory diffuse large B-cell lymphoma, reported no OSD occurrence (42).

Inotuzumab ozogamicin

Two papers focused on side effects and complications of inotuzumab ozogamicin and were included in this review. Also known as Besponsa or InO, inotuzumab is an ADC that was initially approved in 2017 for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). The calcheamicin payload causes double-stranded breaks in DNA, resulting in malignant cell apoptosis. While initially developed and approved for adults who failed treatment with a tyrosine kinase inhibitor, it is now approved for use in treatment naive elderly patients and in clinical trials involving pediatric patients (54,55). While no OSDs have been associated with this drug, a pooled data analysis from the FDA Adverse Event Reporting System (FAERS) from April 2019 to March 2024 found that ocular adverse events with use included conjunctival hemorrhages and eyelid edema. Ocular infections, irritation, and inflammation were also noted; however, the prescribing information for InO does not mention any ocular adverse event development or required eye exams (21). In a combined Phase 1/2 study analyzing the safety and efficacy of InO in patients with relapsed/refractory ALL, one patient in Phase 1 (8.33%) and two patients in Phase 2 (5.71%) reported conjunctival hemorrhages. Blurred vision was also reported in 11% of participants in Phase 1 and 5% of participants in Phase 2 of the same study (22).

Moxetumomab pasudotox

Twelve papers on moxetumomab pasudotox (Lumoxiti) reference side effects and complications with use and two papers that specified ocular side effects were included in our review. Moxetumomab is an anti-CD22 ADC used for the treatment of adults with relapsed or refractory hairy cell leukemia. Lumoxiti works through a PE38 payload, which causes cell apoptosis through ADP-ribosylation of elongation factor 2 inside the cell. In a Phase 1/2 study involving patients with relapsed or refractory B-cell non-Hodgkins lymphoma and chronic lymphocytic leukemia (CLL), one patient (14%) receiving 20 mcg/kg of Lumoxiti reported experiencing blurred vision, and one patient (100%) receiving 60 mcg/kg reported blurred vision (23). In a Phase 3 clinical trial consisting of 80 patients with relapsed/refractory hairy cell leukemia receiving moxetumomab, six patients (7%) reported experiencing dry eye, and seven patients (9%) reported experiencing blurred vision (24).

Brentuximab vedotin

Six papers discussed OSDs associated with brentuximab vedotin and three were included in this review. Brentuximab vedotin (BV/Adcetris) is an ADC used for the treatment of Hodgkins lymphoma and systemic, anaplastic large cell lymphoma. BV targets the CD30 receptor on the surface of activated T and B-cells. After binding and endocytosis, the microtubule-disrupting payload, monomethylastatin E (MMAE), is released via proteolytic cleavage resulting in cell cycle arrest (56).

Ocular side effects are rarely reported with this drug; however, one case of anterior uveitis was reported (18). Ayhan et al. described a patient with Purscher-like retinopathy three weeks after initiating BV therapy for treatment of relapsing Hodgkins lymphoma. Upon diagnosis, brentuximab therapy was discontinued, and the patient was initiated on 1 gram of IV methylprednisolone for 3 days. However, the visual symptoms worsened, and intravitreal injections of 2 mg aflibecept were given. Unfortunately, due to unrelated, pre-existing medical conditions, the patient died six weeks after the diagnosis of the Purscher-like retinopathy (19). Another subject in the same study was found to have bilateral Vogt-Koyanagi-Harada-like granulomatous panuveitis three weeks after initiation of BV for relapsed Hodgkins lymphoma. The patient was started on methylprednisolone 64 mg with a slow taper over 3 months. Due to persistent vitreous floaters and bilateral cataracts, the patient underwent bilateral vitrectomy with complete resolution of all symptoms following surgery (20). Finally, Liu et al. reported of a patient who presented with hyperemia, keratic precipitates, and bilateral anterior and intermediate uveitis. All clinical findings resolved after treatment with topical corticosteroids and mydriatic agents (18).

The proposed pathogenesis of uveitis development with BV use involves dysregulation between activated and regulatory T-cells. While the CD30 receptor is expressed on lymphomatous cells, it is also upregulated on activated T and B-cells. Heiser et al. found that BV selectively depleted T-reg cells when BV was added to a culture of both T-reg and CD8⁺ T-cells. When CD30 expression was analyzed on T-reg and activated CD8⁺ T-cells, it was found that T-reg cells had significantly increased expression of CD30 receptors compared to activated CD8⁺ T-cells. They concluded that the increased expression of CD30 receptors lead to increased endocytosis and higher concentrations of BV inside T-reg cells, resulting in apoptosis (57). The pathophysiology behind honing of activated T-cells to the uvea is not completely understood; however, due to the presence of microtubules in the iris and ciliary body, researchers have theorized that BV-induced uveitis is likely due to an autoimmune process triggered by iris and ciliary body cell destruction by the MMAE payload in the setting of T-cell dysregulation (18,56,58).

Gemtuzumab ozogamicin

Six papers on gemtuzumab ozogamicin (Mylotarg or GO) referenced side effects and complications associated with its use and one paper met criteria to be included in this review. Gemtuzumab is an ADC composed of an anti-CD33 antibody bound to a calicheamicin payload. It is commonly used in the treatment of CD33+ acute myeloid leukemia (AML) and acts by inducing double-strand breaks in DNA (59). Early studies demonstrated promising results with up to 25% of patients demonstrating complete remission when using GO for monotherapy of AML (60).

Dry eye occurred in two patients in a Phase 1b clinical trial analyzing the maximum tolerated dose of patients receiving gemtuzumab and venetoclax, but no ocular adverse events were reported in patients on gemtuzmab alone (26). However, subsequent studies showed no longer rate of remission or overall survival rate in patients taking gemtuzumab compared to standard treatment. A significantly increased risk of fatal non-ocular adverse events was also reported leading to the withdraw of the New Drug Application in 2010 (61,62). More recent studies have demonstrated an increased survival benefit, though, and gemtuzumab was approved by the FDA in 2017 (63).

Polatuzumab vedotin-piiq

Twenty-two papers on polatuzumab vedotin-piiq (Polivy) referenced OSDs associated with its use and one paper was included in this review. Polatuzumab is a novel ADC approved for use in treatment naïve, diffuse large B-cell, high-grade B-cell, and relapsed or refractory diffuse large B-cell lymphomas (64). This drug was also recently approved to be used in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone in adults with untreated diffuse large B-cell lymphoma (65). It is the first ADC to target CD79b and is linked to the anti-mitotic agent MMAE (64). Ocular surface adverse events are rare and predominantly occurred during Phase 1 clinical trials. In a Phase 1B/II clinical study that included 331 patients prescribed polatuzumab in combination with bendamustine and rituximab or obinutuzumab, there was one report of either eye discharge, eye pruritus, glaucoma, and blurred vision. One instance of ocular hyperemia was also reported during Phase 2 of the same trial (25).

Trastuzumab emtansine

Eight papers on traztuzimab emtansine referenced the development of OSDs. Trastuzumab emtansine (T-DM1/Kadcyla) is an ADC commonly used for the treatment of HER2-positive metastatic breast cancer. The mechanism of action of this drug is two-fold. First, trastuzumab binds to the extracellular subdomain of HER2 receptors on malignant cells leading to the downstream effects of microtubule assembly inhibition and interference with intracellular trafficking. Both intracellular mechanisms result in cell death (66).

Several studies have demonstrated the efficacy of T-DM1 in preclinical and clinical trials, with one study in particular (the EMILIA study) demonstrating that patients with HER2-positive breast cancer who took T-DM1 lived on average five months longer compared to those who took standard treatment (10). While the EMILIA study noted no ocular side-effects, other clinical studies have detailed several OSDs associated with T-DM1. Some studies reported only mild ocular effects such as conjunctivitis, photophobia, blurred vision, and increased lacrimation (11-13), while others reported more severe symptoms such as corneal epithelial changes. Tsuda et al. reported a patient who developed irregular, thickened corneal epithelium on the superior and inferior limbal areas after treatment with T-DM1 for 15 months (14). Additionally, Kreps et al. described a patient who developed intraepithelial spherical lesions in the corneal midperiphery and was diagnosed with bilateral corneal epithelial cystoid changes after two doses of T-DM1 (15). In a cross-sectional, prospective study all subjects developed coarse, mid-peripheral cystoid lesions in deep corneal epithelial cells (16).

Epithelial changes associated with T-DM1 appears to be associated with the increased expression of HER2 receptors on the corneal and conjunctival epithelia. Since the HER2 receptor is involved with cellular proliferation and differentiation, inhibition results in cellular arrest and the development of corneal defects (17). The majority of the subjects had resolution of the OSDs after cessation of T-DM1.

Trastuzumab deruxtecan

Forty-five citations were found on trastuzumab deruxtecan-associated OSDs. Of these, three ultimately satisfied inclusion criteria. Trastuzumab deruxtecan (T-DXd or Enhertu), is FDA-approved for the treatment of HER2-positive malignancies, including breast, gastric, and non-small cell lung cancers. On-target toxicity occurs as HER2 is expressed on corneal epithelial cells (6). Trastuzumab deruxtecan may induce oxidative stress in corneal epithelial cells leading to microcystic changes and impaired wound healing (67,68). Additionally, HER2 expression in lacrimal gland tissue may contribute to dry eye syndrome (69). A pharmacovigilance study analyzing the FAERS database identified significant associations between trastuzumab deruxtecan and ocular neuromuscular disorders (70), excessive eye blinking, dry eye syndrome, keratitis, and blurred vision (12). Another FAERS analysis found trastuzumab deruxtecan use was associated with the development of keratopathy and reduced visual acuity (31). A separate pharmacovigilance study of anti-HER2 agents identified asthenopia and abnormal ocular sensations as OSDs occurring with trastuzumab deruxtecan use (32).

Datopotamab deruxtecan

Included in this review was three papers on datopotamab deruxtecan which referenced OSDs. Datopotamab deruxtecan (Datroway or Dato-DXd) is a novel ADC currently approved for patients with metastatic, hormone receptor positive, HER2-positive breast cancer. It is composed of a topoisomerase 1 inhibitor payload covalently linked to a trophoblast cell-surface antigen 2 (TROP2) monoclonal antibody (71). In the phase 3, TROPION-Breast01 study, 21% of patients reported experiencing dry eye, and one patient dropped out of the study due to ocular symptoms. Keratitis was also reported in 14.4% of patients, although the type was not specified (27). An additional safety analysis from this study demonstrated that OSDs were low grade on the CTCAE scale (28). Khoury et al. found that in patients taking datopotamab deruxtecan, 38% of patients experienced ocular adverse effects, including keratitis, blurred vision, photophobia, dry eye, conjunctivitis, and corneal ulcers. However, the researchers reported that all ocular adverse effects were grade 1 or 2, and no patients discontinued therapy due to OSDs (29). The mechanism behind OSD development is unclear, but may be due to the expression of TROP2 receptors on corneal epithelial cells.

Sacituzumab govitecan

Two publications assessed OSD development with sacituzumab govitecan use. Sacituzumab govitecan (SG or Trodelvy), is a TROP-2-directed ADC approved for metastatic, triple-negative breast cancer and hormone receptor positive/HER2-negative metastatic breast cancer (72). The payload is SN-38, a topoisomerase I inhibitor, is speculated to have limited corneal epithelial penetration (73). Given this, OSDs are rare and typically mild. Pooled safety data from four clinical trials including 1,063 patients revealed no significant ocular toxicity. The ASCENT Trial in 267 subjects with metastatic triple negative breast cancer found 5% of patients experienced low-grade dry eyes and blurred vision (33). In the phase 2 TROPHY-U-01 Trial of 113 patients, 4% of patients reported mild conjunctival irritation (34). A 2022 review noted isolated cases of periorbital edema, although the frequency was not reported (74).

Enfortumab vedotin

Fifteen studies focused on enfortumab vedotin-associated OSDs and one was included in this review. Enfortumab vedotin (EV or Padcev) is an ADC that binds to Nectin-4, a protein overexpressed in urothelial carcinoma cells and is linked to the cytotoxic agent MMAE which induces apoptosis (75). The exact pathophysiology of OSDs remains under investigation; however, on-target toxicity due to Nectin-4 expression in ocular tissues and off-target effects from the cytotoxic payload MMAE may lead to the corneal epithelial damage (74). Commonly reported symptoms included dry eye, blurred vision, keratitis, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy (75,76). Thibodeau and Nallasamy [2021] reported visually significant, bilateral, anterior subcapsular cataract development and dry eye syndrome following therapy with enfortumab vedotin (30).

Belantamab mafodotin

Five papers reporting of OSDs with belantamab vedotin use were included in this review. Belantamab mafodotin (Blenrep) is a B-cell maturation antigen (BCMA)-targeted ADC for relapsed or refractory multiple myeloma (RRMM) (77,78). While systemically well tolerated, OSDs were the most commonly reported adverse event reported in clinical trials. The payload, monomethyl auristatin-F (MMAF), disrupts microtubule formation. The off-target delivery occurs through macropinocytosis of the drug by corneal stem cells at the corneoscleral limbus or through tear film absorption. Corneal epithelial cells undergo apoptosis after MMAF endocytosis (77,79). In the DREAMM-1 and DREAMM-2 trials, ocular toxicity occurred in 53–75% of patients, with keratopathy or microcyst-like epithelial changes (MECs) observed in 72% of patients at the 2.5 mg/kg dose (77,78). In the DREAMM-2 trial of 223 patients, the most common symptoms, blurred vision and dry eyes, were seen in 58% of patients, with 18% requiring treatment discontinuation due to ocular events (38). The DREAMM-3 and DREAMM-6 trials confirmed similar trends with keratopathy being the most common, non-hematologic adverse event (36,37). Similarly, in a study by Gallin et al. [2025], nine patients exhibited hyporeflective lesions on infrared reflectance imaging of the anterior segment, indicative of corneal toxicity corresponding to keratopathy with corneal MECs observed on slit-lamp examination (35). Severe cases (grade ≥3) of MECs involve corneal ulcers or best corrected visual acuity (BCVA) decline to ≤20/50 (35,38). A real-world multicenter retrospective study by Patel et al. showed that over 80% of patients developed adverse ocular events, and 49% required dose modifications (39). Due to the risk of ocular toxicity, belantamab carries a black box warning. Patients receive routine monitoring, which involves comprehensive eye exams at baseline, before each treatment, within one week after the final dose, and two weeks prior to the subsequent dose, as well as immediate evaluation for any new or worsening visual symptoms (38).

Tisotumab vedotin

Three papers discussed tisotumab vedotin-associated OSDs. Tisotumab vedotin (TV or Tivdak) is an ADC comprising a tissue factor (TF)-directed monoclonal antibody conjugated to MMAE and it is approved as a second or third-line agent for recurrent or metastatic cervical cancer (43). TF is also expressed in conjunctival vascular endothelial cells (44,80). OSDs were reported in 55% of 425 patients in the phase 2 innovaTV 204 clinical trial (45). Due to the risk of ocular toxicity, tisotumab carries a black box warning. Manifestations include conjunctivitis (32%), dry eye (24%), keratopathy (17%), and corneal ulceration (2.1%). Severe ocular surface disorders were identified in a small proportion of patients, with approximately 3.3% experiencing grade 3 events. Other less common findings included conjunctival ulcers, corneal and conjunctival erosions, and symblepharon with each affecting less than 2% of patients (45). In a case series by Lent-Schochet et al., subepithelial fibrosis and conjunctival scarring developed in 5 patients (44). Similarly, in the innovaTV 301 trial, three patients developed ulcerative keratitis while one subject developed each OSD: keratitis, punctate keratitis and corneal erosion, blepharitis and conjunctival hyperemia, conjunctival scar, and conjunctivitis and xerophthalmia (81).

Mirvetuximab soravtansine

Four studies reported mirvetuximab soravtansine-associated ocular surface effects. Mirvetuximab soravtansine (MIRV or Elahere), is the first FDA-approved ADC for folate receptor alpha (FRα)-positive, platinum-resistant epithelial ovarian cancer. The ADC consists of an anti-FRα monoclonal antibody linked to the cytotoxic payload DM4, a maytansinoid derivative, that is endocytosed into corneal epithelial cells (82). Intracellular accumulation of DM4 triggers apoptosis and formation of subepithelial pseudomicrocysts as the pathogenesis of this off-target toxicity (46). A pooled safety analysis of 464 patients treated with MIRV across three clinical trials, including the phase 2 SORAYA study, revealed that ocular surface disorders were reported in more than 50% of patients in the clinical trials (83,84). A black box warning was added in the prescribing information on the need for baseline and every other cycle ocular exams to assess for the development of OSDs and to prevent vision loss (84).

OSDs generally appear early in treatment, are mostly mild in severity, and tend to be reversible (83). In the phase 2 (SORAYA) and phase 3 (MIRASOL) trials, reported rates of OSDs of any grader were: blurred vision (41–43%), keratopathy (32–36%), and dry eye syndrome (25–28%). Collectively, these OSDs often requiring dose reductions, dose delays or discontinuation of treatment altogether (47,48). No increase in the severity of OSD grade was seen over the treatment duration (49).

Telisotuzumab vedotin

Post-screening, four papers referenced telisotuzumab vedotin and the development of OSDs. Telisotuzumab vedotin, also known currently as Emrelis, is a novel c-Met-directed ADC granted accelerated FDA approval in May 2025 for advanced non-small cell lung cancer (85). Telisotuzumab vedotin contains the payload MMAE leading to cellular apoptosis, impaired wound healing, and in the cornea, MECs (50,86). In the Phase 1b trial of 52 patients, OSDs included blurred vision (4%) and conjunctivitis (3%) (51). Similarly, a Phase I study from Japan reported reversible dry eye syndrome and conjunctivitis that did not necessitate treatment discontinuation (52). In the phase 2 LUMINOSITY trial of 172 patients, OSDs occurred in only 10–15% of subjects (50). The most frequently observed OSDs were mild and included blurred vision (15%), keratitis (11%), and dry eye (5%) (50,53).

While ADC efficacy is well-documented, emerging evidence highlights the variable occurrence of OSDs and the significant impact on quality of life. Early recognition and intervention can mitigate OSD progression, enabling patients to continue ADC therapy. A comparative summary of approved ADCs, their molecular targets, therapeutic indications, reported ocular side effects and incidence rates of OSDs provides further context to the mechanisms underlying these adverse events (Table 2). Additionally a breakdown of the most commonly reported OSDs by ADC highlights key symptoms that providers and patients should observe when prescribed these medications (Table 3).

Discussion

Previous studies have provided in-depth analysis on the pathophysiology, mechanism and treatment regimen for OSDs caused by ADCs. The FAERS study found 2,686 adverse events associated with ADCs, noting that some ADCs were more likely to cause OSDs than others (21). Dy et al. discussed typical adverse events in patients taking ADCs as well as treatment strategies for these patients (6). Additionally, Eaton et al. detailed the evolution of ADCs and their associated adverse events, highlighting that OSD monitoring should evolve along with changing ADCs (67). While these studies offer valuable information for physicians and patients, they vary in methodology, reported incidence, and spectrum of reported adverse events, making it challenging to provide accurate and up to date information to patients. Our review, utilizing a standardized protocol with strict inclusion and exclusion criteria, provides uniformity to limit variability and ensure that patients are given accurate, evidence-based information.

The rates of OSD occurrence vary by ADC and predominately involve the corneal epithelium, clinically resulting in the development of dry eye disease to MECs. Despite variations in payload, linker stability, and target antigens, prevention and screening remain essential for early diagnosis of OSDs. Clinicians should maintain heightened awareness when prescribing ADCs known to cause OSDs, namely belantamab mafadotin, mirvetuximab soravtansine and tisotumab vedotin. An awareness of the most frequent OSDs associated with each ADC is also important as this gives both providers and patients information on key symptoms to observe. For example, belantamab mafadotin most commonly causes keratopathy while dry eye is most commonly reported with sacituzumab govitecan (33,77). While specific ADCs have standardized screening and post-infusion mitigation protocols (mirvetuximab, tisotumab, and belantomab), patients initiated on all ADCs should receive a baseline ophthalmic exam to determine those most at risk for development of OSDs. Prophylactic measures such as artificial tears, cold compresses, and in certain cases topical steroids can be recommended to patients to reduce the severity of symptoms. Additionally, patients should be urged to avoid contact lens use and ensure treatment of underlying conditions such as ocular rosacea and blepharitis that can exacerbate OSDs. During treatment, patients should be encouraged to undergo frequent eye exams after every ADC cycle, or sooner if new symptoms develop. Management of OSDs largely depends on the specific surface dysfunction. Namely, artificial tears and warm compresses should be recommended for dry eye, while lid hygeine with topical antibiotics and possible steriods should be prescribed for blepharitis. Treatment interruption should be considered in patients with grade ≥2 adverse events until improvement to grade ≤1 (6,21,32,75).

Mitigation protocols, particularly those involving topical corticosteroids and lubricating eye drops, have been implemented to decrease the occurrence of ADC-associated OSDs (77). In addition, the multidisciplinary collaboration between oncologists and ophthalmologists needs to occur to ensure patients receive baseline, post-infusion, and as needed slit lamp examinations. Early detection and continued monitoring not only identifies OSDs at a potentially milder grade but also preserves visual function (35). An ocular review of systems and reminders to return to the ophthalmologist for intraocular pressure and lens status checks, with use of topical corticosteroids, can be performed by oncology team. Experience with belantamab mafodotin exemplifies the complex risk-benefit profile of ADCs. Although the drug was voluntarily withdrawn from the U.S. market in 2022 due to concerns over efficacy, it continues to be evaluated in global trials such as DREAMM-7 and DREAMM-8, where researchers are exploring combination therapies that maintain therapeutic potency while minimizing ocular toxicity (88,89).

Similarly, the FDA added a black box warning to the prescribing information for tisotumab vedotin with a mitigation strategy consisting of several steps. Instillation of vasoconstrictive drops prior to and the application of cold packs during the infusion limit delivery of tisotumab to the ocular surface (45). The current protocol which has been shown to reduce the incidence and severity of OSDs, includes the administration of topical corticosteroid eye drops during the infusion and continuing for the subsequent 72 hours. To prepare for the infusion, vasoconstrictor eye drops are typically applied at a dosage of three drops per eye immediately before the infusion. In addition, over-the-counter lubricating eye drops are recommended for use as needed throughout the entire course of therapy and for at least 30 days following the final dose of tisotumab, in order to maintain ocular comfort and hydration (45). Again, close collaboration between the oncologist and the ophthalmologist is needed to ensure ocular exams are completed prior to the first 9 cycles of tisotumab and communication if dose modifications or holds are needed until the OSD returns to grade 1 or less (44,81). A mitigation strategy for treatment and screening slit lamp examinations has also been set forth by the FDA for mirvetuximab soravtansine. Unlike tisotumab, slit lamp examinations need to occur every other cycle for the first 8 cycles (49,82). Post-infusion, a prescribed regimen combining preservative-free lubricating eye drops and corticosteroid drops are tapered over a several day period has been shown to help reduce the risk of ocular toxicity (6,83).

Despite the burgeoning knowledge on adverse events associated with ADCs, a complete understanding of the mechanisms behind the development of OSDs is lacking. Approval of new ADCs requires an understanding of the ocular adverse events associated with the drugs. In addition, the rate of occurrence of several OSDs were difficult to quantify due to lack of granularity in the current literature (21,30,36,39,47,77). More after market or large electronic health record-based studies are needed to determine the real-world incidences of OSDs with ADC use. Future research should be aimed at exploring ways to make the CTCAE more granular to discern between adverse events, such as dry eyes or watering eyes, along with additional adverse event descriptions including conjunctivitis to accurately diagnose the OSDs (8). Additionally, there is currently no standardized treatment paradigms for OSDs or agents designed to prevent uptake of the ADC into ocular tissues. As the future therapeutics continue to evolve, the implementation of standardized ocular toxicity prevention, monitoring, and treatment protocols will be necessary to optimize patient outcomes. Education must be provided to patients prescribed ADCs on symptoms monitoring and when to call their ophthalmologist. Proper eye drop instillation instructions should also be provided. Effective interdisciplinary collaboration between ophthalmologists and oncologists not only preserves visual function but also ensures that life-prolonging oncologic therapies can be delivered without unnecessary interruption due to avoidable ocular complications.

Conclusions

ADCs have emerged as a promising class of targeted therapies across a wide range of malignancies. However, the on and off-target toxicities on the ocular surface vary by agent and severity. The most common OSDs include keratitis, dry eye syndrome, conjunctivitis, blurred vision, and corneal epitheliopathy. Although most ocular toxicities are reversible, their potential to impair visual function and disrupt oncologic treatment necessitates the need for systematic surveillance.

Our review highlights critical clinical implications for future ADC use. First, the incorporation of standardized ophthalmic monitoring before and during therapy is essential, particularly as ADCs move earlier in treatment algorithms and into broader indications. Evidence supports the routine use of baseline ocular examinations and periodic slit-lamp assessments to facilitate timely intervention. Second, mitigation strategies, such as lubricating and corticosteroid eye drops, should be consistently implemented to reduce the incidence and severity of ocular events.

These findings also have implications for clinical policy and ADC development. Uniform ocular-toxicity management guidelines across institutions are needed. Patient education should revolve around symptom identification and adherence to prophylactic measures. Close communication between oncology and ophthalmology is needed to coordinate care and infusion timing. As ADC pipelines continue to expand, prospective monitoring and standardized prevention strategies will be essential to optimize patient outcomes and preserve visual function.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Roy S. Chuck, Joann J. Kang and Viral V. Juthani) for the series “Inflammatory Disorders of the Cornea and Ocular Surface” published in Annals of Eye Science. The article has undergone external peer review.

Reporting Checklist: The authors have completed the PRISMA-ScR reporting checklist. Available at https://aes.amegroups.com/article/view/10.21037/aes-25-45/rc

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-25-45/prf

Funding: None.

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