Managing Microcyst-Like Epithelial Keratopathy Related to Cancer Therapy

Antibody-drug conjugates (ADCs) are a new class of targeted drugs for cancer therapy and comprise a monoclonal antibody bound to a cytotoxic payload using a chemical linker. ADCs allow targeted delivery of a highly potent anti-cancer agent to the tumor with limited damage to surrounding healthy cells. However, each ADC carries its own set of toxicities.

Mirvetuximab soravtansine-gynx injection 100 mg (Elahere, ImmunoGen) offers a new option for patients with certain types of ovarian cancer and is the first FDA-approved therapy for this malignancy since 2014.¹ Because mirvetuximab is associated with ocular adverse events (AEs), the patient’s ability to remain on mirvetuximab therapy is maximized by effective partnerships between optometrists and oncologists.

EPITHELIAL OVARIAN CANCER

Epithelial ovarian carcinoma (EOC) is estimated to cause 13,270 deaths in the United States in 2023.² Most patients with EOC initially respond to platinum-based chemotherapy; however, up to 80% of patients experience recurrence and eventually develop platinum-resistant ovarian cancer (PROC).³ EOC is characterized by aberrant overexpression of folate receptor alpha (FRα), which is absent in normal ovarian epithelium and constitutively expressed in 80% to 96% of ovarian tumors.^4,5 There are limited non-platinum–based options for treating PROC, and those have systemic side effects, including nausea, vomiting, muscle pains, myelosuppression, peripheral neuropathy, and alopecia.^6-8

A NOVEL TREATMENT

Mirvetuximab is a first-in-class ADC comprising an FRα-targeted antibody conjugated to a cytotoxic payload (DM4) via a cleavable disulfide linker.⁹ After mirvetuximab is internalized by FRα-positive tumor cells, active DM4 catabolites are released to induce cell cycle arrest and apoptosis via inhibition of microtubule assembly.^8-10

ADCs with tubulin-targeting payloads are associated with ocular surface AEs.¹¹ Although microcyst-like epithelial keratopathy may be observed with several ADCs comprised of tubulin-targeting payloads, differences in antibody target, specific payload, and linker affect the frequency, severity, and specificity of ADC-associated ocular AEs.^7,12,13 Accordingly, eye care management strategies vary across product labels.⁷ Most mirvetuximab-associated ocular AEs are low-grade corneal events that are resolvable with supportive care for symptoms and dose modifications when indicated.¹⁴

Mechanism of Mirvetuximab-Associated Corneal Events

Because FRα is not expressed in the corneal epithelium, mirvetuximab is thought to be internalized via a non-receptor–mediated mechanism; therefore, its antimitotic effect on dividing cells in the corneal epithelium is assumed to be “off-target.”¹¹ Mirvetuximab is thought to reach the cornea via the vascularized limbal region and/or via the tear film.^11,15 Microcystic-like epithelial changes (MECs) may be observed in the perilimbal cornea at the level of the basal epithelium and can potentially advance to the central cornea.¹¹ These MECs may be associated with transient changes in corneal topography, which may present with blurred vision,¹⁶ with or without superficial punctate keratopathy and dry eye sensation.

Clinical Trial Information

In November 2022, mirvetuximab received accelerated FDA approval based on SORAYA, a single-arm trial of 106 adult patients with FRα-positive PROC who had received one to three prior systemic treatments.¹⁷ Continued approval is contingent on results from the confirmatory MIRASOL trial.^18,19 A pooled safety population reflects exposure to mirvetuximab in 464 patients across three clinical trials, including SORAYA.¹⁹

Safety Outcomes

As with other targeted therapies, mirvetuximab is associated with ocular AEs, including low-grade corneal or vision-related AEs,^{7,11,14,17,20-22} and incidence of ocular AEs increases with increasing mirvetuximab exposure.²³ The product labeling for mirvetuximab includes a boxed warning for ocular toxicity.¹⁹

Ocular AEs (> grade 3) occurred in 9% of patients treated with mirvetuximab in the pooled safety population (Table 1). Of these, 49% had complete resolution and 39% had partial resolution (defined as a decrease in severity by 1 or more grades from the worst grade) at last follow-up.¹⁹ Blurred vision was associated with moderate and resolvable keratopathy characterized by transient microcyst-like changes to corneal epithelium.²² There were no corneal ulcers, perforations, or permanent ocular sequelae.^22,24 Ocular AEs led to permanent discontinuation of therapy in fewer than 1% of patients.^17,19

Mirvetuximab is administered by intravenous infusion on day 1 of a 3-week treatment cycle. The first ocular AE occurred around the second infusion (median, 1.2 months; range, 0.03 – 12.9 months).¹⁹

Management of Ocular AEs

An eye care management plan for mirvetuximab therapy has been established and is reflected in US product labeling to include the use of pre-treatment eye drops, ophthalmic monitoring, and dose modifications by the patient’s oncologist (Table 2). Thorough assessment of baseline ocular health and refractive status by an optometrist allows later differentiation of treatment-related ocular AEs from preexisting ocular conditions.^17,19

Prophylactic use of ophthalmic topical steroids is recommended. In SORAYA, patients were prescribed prednisolone acetate 1% ophthalmic suspension or equivalent, dosed as described in Table 2. It is hypothesized that steroids may reduce the rate of proliferation of corneal epithelial cells, making them less susceptible to antimitotic agents, such as DM4.¹¹ Frequent lubrication with preservative-free artificial tears is also recommended and has been shown to reduce the frequency and severity of mirvetuximab-related ocular events.⁷ Patients are advised to avoid contact lens wear during treatment with mirvetuximab, unless directed by their eye doctor. These measures do not completely eliminate the development of ocular AEs, and additional ophthalmic mitigation strategies are being investigated.^7,11,19

Patients are referred to their optometrist for scheduled follow-up as described in Table 2. Mirvetuximab dosage modifications (to delay, reduce, or permanently discontinue treatment based on severity and persistence of symptoms) are also an important tool for mitigation of ocular AEs.^7,11 Although nonconfluent keratopathy without significant (≥ 3 line) reduction in BCVA requires only monitoring, ophthalmic examination findings are used to guide dose modification decisions by the oncologist in response to significant corneal findings, meaningful changes in BCVA, and other ocular AEs (Table 3). The goal is to enable prompt intervention with dosage modification by the oncologist to limit unnecessary discontinuations in treatment. Dose modifications are made by the oncologist based on ocular examination findings (Table 3).

THE OPTOMETRIST’s ROLE

Optometrists play a central role in the collaborative management of these patients by accurately diagnosing and characterizing mirvetuximab-related ocular findings, providing supportive care to manage symptoms of ocular AEs, and ensuring compliance to the eye care regimen. Critically, the optometrist is responsible for communicating findings of mirvetuximab-related ocular AEs to the oncologist to provide appropriate dosage modifications in the context of the patient’s overall health status. Partnering with the oncology care team to ensure an effective line of communication between the optometrist and the oncologist is critical to mitigating mirvetuximab-associated ocular AEs and ensuring optimal outcomes for patients undergoing mirvetuximab therapy.