Ocular Surface Adverse Events and Changes Related to Antibody-Drug Conjugates
MECs are bilateral lesions of the corneal epithelium associated with antibody-drug conjugates (ADCs), also known as immunoconjugates  . ADCs are a novel class of anticancer drugs with four approved agents and numerous ongoing clinical trials . Ocular toxicity in the form of MECs is one of the most frequently reported adverse events (AEs) of ADCs.
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). Corneal toxicity is one of the most common adverse events (AE) associated with ADCs. Through unknown mechanisms, ADCs lead to the formation of epithelial inclusions that begin near the limbus and extend centrally as drug dosage and duration of therapy increase (Figure 2). These changes are termed “microcyst-like” because they are not felt to represent true microcysts. Instead, in vivo confocal microscopy (IVCM) has demonstrated the presence of round, hyperreflective intracellular structures most prominent in the basal layer of the epithelium (Figure 3). 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 . MECs occur bilaterally. Patients may complain of symptoms such as irritation, blurred vision, and tearing, although often patients are asymptomatic. Diminished visual acuity and subjective feelings of blurred vision may be correlated with more centrally located MECs     . Symptoms and corneal changes largely resolve with discontinuation or tapering of the offending agent. Artificial tears, steroid eye drops, epithelial debridement, or serum tears have been reportedly used as adjunctive therapy in an attempt to ameliorate MEC formation  . Collectively, the reported findings suggest that MEC containing cells are replaced with healthy cells as the corneal epithelium regenerates upon temporarily holding or stopping the drug.
Patients with a history of dry eye prior to starting a course of ADCs may be predisposed to the development of MECs. Formation and progression of MECs do appear to be dose dependent and are largely reversible with dose modifications or increasing the interval between infusions. Resolution of symptoms and regeneration of the corneal epithelium can vary from weeks to months.
Limbal stem cells normally form new epithelial cells that migrate centripetally, starting in the peripheral basal epithelium. Basal epithelial cells differentiate into wing cells and subsequently superficial epithelial cells. MECs are small, microcyst-like lesions associated with ADCs that begin near the limbus or mid-peripheral cornea and travel centrally  . IVCM of corneas with MECs reveals the presence of hyperreflective structures most prominent in the basal epithelium and wing cells  (Figure 3). These structures may potentially represent internalization of the drug within epithelial cells in various stages of apoptosis Taken together, a plausible mechanism for MEC formation is that ADCs enter limbal stem cells through the limbal circulation and then damage differentiating epithelial cells  .
In a recent case series by Kreps et al. of two patients who developed MECs 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.
Corneal epithelial cells theoretically undergo ADC-induced cell death, facilitating further (peripheral) MECs 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. Two proposed mechanisms for ADC-mediated damage are on- versus off-target toxicity. On-target toxicity may occur via receptor-mediated endocytosis in corneal 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 4).
Prophylactic topical corticosteroids have not shown a clear benefit in preventing or treating ocular adverse effects of ADCs, including MECs. Preservative-free lubricating eye drops have been recommended, although a benefit has not been demonstrated thus far.
Patients may complain of dry eye symptoms such as irritation, tearing, foreign body sensation, or blurred vision. As MECs invade the central corneal epithelium, patients may demonstrate an objective decrease in visual acuity. Often, patients will have MECs in the peripheral cornea but deny any ocular symptoms    .
Slit lamp examination will show multiple tiny, translucent epithelial inclusions most notable in the cornea periphery. They are best observed using retroillumination or indirect illumination on high magnification. These lesions can progress centrally. A whorl-like pattern of fluorescein staining is sometimes seen under cobalt blue light, and does not necessarily correlate with the pattern of MECs (Figure 5). A recent grading system was developed by Farooq, et al. based on MEC severity and visual acuity with guidelines for treatment modification for the drug belantamab mafodotin, an ADC used to treat multiple myeloma (Table 1).
In vivo confocal microscopy
In vivo confocal microscopy (IVCM) shows round, hyper-reflective material that is most prominent in the cornea basal epithelium and wing cells. There is relative sparing of the superficial epithelium, and no material is seen within the stroma or endothelium. MECs, therefore, are not felt to represent true cysts  (Figure 3). It is unclear as to what these hyper-reflective structures are, but they may be epithelial cells with internalized ADCs, and in various stages of apoptosis.
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 artificial tears. Topical corticosteroids may be considered  .
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.
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 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)   .
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 1). Table 1 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. With Grade 1 changes, doses are continued. With Grade 2 and 3, treatments are held until the exam improves to Grade 1, with Grade 3 requiring a reduced dose once restarted. With an epithelial defect and/or BCVA <20/200 (Grade 4 on the KVA scale), an alternative treatment should be considered unless the benefits truly outweigh the risks. Corneal changes from this and other MMAF-containing ADCs were reversible with treatment cessation, often showing resolution from a few weeks to several months .
MECs largely resolve with discontinuation or tapering of the offending agent as MEC containing cells are replaced with healthy, regenerated cornea epithelium.
- 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).
- Lee BA, Lee MS, Maltry AC, Hou JH. Clinical and histological characterization of toxic keratopathy from depatuxizumab mafodotin (ABT-414), an antibody-drug conjugate: 2021 Sep 1;40(9):1197-1200
- Gan HK, Reardon DA, Lassman AB, et al. Safety, pharmacokinetics, and antitumor response of depatuxizumab mafodotin as monotherapy or in combination with temozolomide in patients with glioblastoma. Neuro Oncol. 2018;20:838–47.
- Thompson JA, Motzer RJ, Molina AM, et al. Phase I trials of anti-ENPP3 antibody-drug conjugates in advanced refractory renal cell carcinomas. Clin Cancer Res. 2018;24:4399–406.
- Younes A, Kim S, Romaguera J, et al. Phase I multidose escalation study of the anti-CD19 maytansinoid immunoconjugate SAR3419 administered by intravenous infusion every 3 weeks to patients with relapsed/refractory B-cell lymphoma. J Clin Oncol. 2012;30:2776–82.
- Deklerck E, Denys H, Kreps EO. Corneal features in trastuzumab emtansine treatment: not a rare occurrence. Breast Cancer Res Treat. 2019;175:525–30.
- Tannir NM, Forero-Torres A, Ramchandren R, et al. Phase I dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma. Invest New Drugs. 2014;32:1246–57.
- Bashraheel SS, Domling A, Goda SK. Update on targeted cancer therapies, single or in combination, and their fine tuning for precision medicine. Biomed Pharmacother. 2020;125:110009.
- Eaton JS, Miller PE, Mannis MJ, Murphy CJ. Ocular adverse events associated with antibody-drug conjugates in human clinical trials. J Ocul Pharmacol Ther. 2015;31:589–604.
- Corbelli E, Miserocchi E, Marchese A, et al. Ocular toxicity of mirvetuximab. Cornea. 2019;38:229–32.
- Kreps EO, Derveaux T, Denys H. Corneal changes in trastuzumab emtansine treatment. Clin Breast Cancer. 2018;18:e427–e429429.
- De Goeij BE, Lambert JM. New developments for antibody-drug conjugate-based therapeutic approaches. Curr Opin Immunol. 2016;40:14–23.
- Mahalingaiah PK, Ciurlionis R, Durbin KR, et al. Potential mechanisms of target-independent uptake and toxicity of antibody-drug conjugates. Pharmacol Ther. 2019;200:110–25.
- Antoun J, Titah C, Cochereau I. Ocular and orbital side-effects of checkpoint inhibitors: a review article. Curr Opin Oncol. 2016;28:288–94.
- Heinzerling L, Eigentler TK, Fluck M, Hassel JC, Heller-Schenck D, Leipe J, et al. Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management. ESMO Open. 2019;4:e000491.
- Huillard O, Bakalian S, Levy C, Desjardins L, Lumbroso-Le Rouic L, Pop S, et al. Ocular adverse events of molecularly targeted agents approved in solid tumours: a systematic review. Eur J Cancer.v2014;50:638–48.
- Goss GD, Vokes EE, Gordon MS, et al. Efficacy and safety results of depatuxizumab mafodotin (ABT-414) in patients with advanced solid tumors likely to overexpress epidermal growth factor receptor. Cancer. 2018;124:2174–83.
- van den Bent M, Gan HK, Lassman AB, et al. Efficacy of depatuxizumab mafodotin (ABT-414) monotherapy in patients with EGFR-amplified, recurrent glioblastoma: results from a multi-center, international study. Cancer Chemother Pharmacol. 2017;80:1209–17.
- Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21:207–21.
- Banerji U, van Herpen CML, Saura C, et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 2019;20:1124–35.