Bilateral Anterior Subcapsular Cataract Development Following Initiation of Enfortumab Vedotin

Introduction

Cataract is the leading cause of reversible blindness in the world.¹ Aging, genetics, systemic disease, trauma, inflammation and toxic exposure are all known contributors to cataract development, with strong associations for particular cataract subtypes.² Commonly classified by location and morphology of the lens opacity, cataract subtypes include nuclear, cortical, subcapsular and combined. Anterior subcapsular cataract formation results from fibrous metaplasia of the lens epithelium and is associated with ocular trauma, inflammation or irritation. Cataracts may cause varying degrees of visual impairment depending on location and severity. When a patient develops a significant decline in visual functioning or reduction in quality of life, surgical intervention may be considered.

In December 2019, the US Food and Drug Administration granted accelerated approval for enfortumab vedotin, a Nectin-4 targeting antibody–drug conjugate indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer. We report a case of visually significant bilateral anterior subcapsular cataract development following therapy with enfortumab vedotin. While the exact mechanism remains to be elucidated, patients and physicians should be aware of the risk of anterior subcapsular cataract formation following enfortumab vedotin initiation.

Case Description

A 62-year-old male with a history of metastatic urothelial carcinoma was enrolled in NCT03288545, a phase 1b national clinical trial designed to examine the safety, tolerability and efficacy of enfortumab vedotin alone and in combination with other anticancer therapies. The patient was initiated on enfortumab vedotin in combination with cisplatin. The study began on October 11, 2017, and is estimated to run until December 31, 2026.³ The patient had no past ocular history and baseline eye exam demonstrated a best-corrected visual acuity of 20/20 in both eyes. He was noted to have transparent crystalline lenses and an unremarkable anterior and posterior segment examination. While undergoing treatment, the patient noticed a gradual decline in his vision. Repeat examination 18 months after initiation of therapy demonstrated a two-line decrease in best-corrected visual acuity that was further reduced to 20/60 and 20/200, respectively, upon glare testing. Slit-lamp examination revealed interval development of bilateral, symmetric 2–3+ anterior subcapsular and 1+ posterior subcapsular cataracts (Figure 1). Over this same time frame, the patient received intermittent low-dose (5–10 mg) oral prednisone in addition to systemic dexamethasone with his chemotherapy infusions. Both enfortumab vedotin and cisplatin were administered at their standard recommended doses. He had no history of radiation therapy or diabetes. After discussion of options regarding his visually significant cataracts, the patient elected to proceed with phacoemulsification and intraocular lens implantation for both eyes. Post-operatively, he noted significant improvement in his vision and best-corrected visual acuity measured 20/20 for each eye.

Figure 1 Retroillumination slit-lamp photograph highlighting the anterior subcapsular opacification of the crystalline lens involving the visual axis of the left eye after 18 months of therapy with enfortumab vedotin.

Discussion

Enfortumab vedotin directly targets Nectin-4, an adhesion protein highly expressed in bladder cancer cells. Following endocytosis, the complex releases monomethyl auristatin E, a microtubule-disrupting agent that induces cell cycle arrest and, ultimately, apoptotic cell death.⁴ Safety data from Phase I and Phase II clinical trials prompted early warnings of the possibility of ocular disorders with enfortumab vedotin therapy.^4,5 In these studies, 46% of the 310 patients treated developed ocular side effects.⁶ Most events were attributable to ocular surface disease, with dry eye symptoms reported in 36% of patients and blurred vision in 14%. There was a median time of 1.9 months to symptom onset and no report of cataract development.⁴ Since approval in 2019, there have been multiple case reports of adverse cutaneous reactions related to enfortumab vedotin use; however, there have been no published reports of adverse ophthalmic effects attributed to the drug.^7–10

Anterior subcapsular cataract results from fibrous metaplasia of the lens epithelium. This type of lens opacification is associated with ocular trauma, inflammation or irritation; atopic dermatitis, electrical burn and irradiation are typical scenarios.¹¹ Our patient did not manifest any clinical signs or conditions known to be associated with anterior subcapsular cataract development. Additionally, cisplatin, our patient’s only other new medication exposure, has been in medical use for over four decades and is not associated with cataract formation. His intermittent systemic steroid use likely contributed to the development of the posterior subcapsular component of his cataracts. Steroids are a well-established risk factor for posterior subcapsular cataracts but not for anterior subcapsular cataracts.

To the best of our knowledge, this is the first reported case of anterior subcapsular cataract formation as a consequence of enfortumab vedotin therapy. Histologic evidence shows that transforming growth factor-β (TGF-β) plays a critical role in lens epithelial cell proliferation and epithelial–mesenchymal transition. Inappropriate TGF-β signaling with subsequent accumulation of extracellular matrix is strongly implicated in anterior subcapsular cataract pathogenesis.¹² It is possible that enfortumab vedotin cross-reactivity with Nectin-3, which is expressed in the anterior epithelial cells of the crystalline lens, may contribute to this process.¹³ Although not routinely performed, utilization of immunohistochemical staining to detect Nectin-4 and Nectin-3 expression on the anterior lens capsular tag could help elucidate the mechanism of action for anterior subcapsular cataract formation. Given the irreversible nature of cataracts and the need for surgical intervention to restore vision, pre-treatment counseling regarding this adverse effect of enfortumab vedotin is warranted.

Conclusion

Blurry vision, dry eye and anterior subcapsular cataract development are potential adverse effects of enfortumab vedotin. A baseline eye exam is recommended for all patients who start enfortumab vedotin. Patients should monitor for vision changes while undergoing therapy.