Cancer remains the second-leading cause of death in the United States.¹ Although traditional treatments include surgical resection, radiation, and chemotherapy, the role of targeted immunotherapy in the treatment of these patients continues to grow. Greater understanding of the specific tumor antigens and signaling pathways has led to novel cancer therapeutics that use the patient’s own immune system to identify and attack cancer cells. These therapies are now commonly used to treat a variety of malignancies, including metastatic melanoma, renal cell carcinoma, colon cancer, and lung cancer, and they have led to a significant reduction in mortality.

Although targeted immunotherapies are generally better tolerated than chemotherapy, several ocular toxicities have been described across the various classes of agents. This article will describe retinal toxicities of checkpoint inhibitors, protein kinase B-raf (BRAF) inhibitors, and mitogen-activated extracellular kinase (MEK) inhibitors.

Checkpoint Inhibitors 

The most common subset of immunotherapies, immune checkpoint inhibitors (ICIs) upregulate the immune system to more effectively target cancer cells. Immune checkpoint proteins such as cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4), program cell death receptor 1 (PD-1), programmed cell death ligand 1 (PD-L1), and lymphocyte activation gene-3 (LAG-3) suppress T-cell function when bound and serve as an “off switch.” Immune checkpoint inhibitors block these proteins to enhance T-cell immune response against cancer cells. Currently, FDA-approved ICIs include CTLA-4 inhibitors (ipilimumab and tremelimumab), PD-1 inhibitors (cemiplimab, dostarlimab, nivolumab, pembrolizumab, retifanlimab, tislelizumab, and toripalimab), PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab), and LAG-3 inhibitors (relatlimab). ICIs are used to treat a broad range of cancers, including melanoma, non-small cell lung cancer, colorectal cancer, hepatocellular cancer, renal cell cancer, and others.²

Ocular immune-related adverse events (irAEs) have been reported to occur in up to 1% of patients treated with ICIs.^3,4 Though less common, retinopathy made up 13% of all ocular irAEs in one study.⁵ Although rare, their impact continues to grow as new drugs are approved and indications for their use expand. The most common ocular irAEs are uveitis and dry eye, typically developing within the first few weeks to months of therapy.^6,7

A Vogt-Koyanagi-Harada (VKH)–like syndrome with bilateral panuveitis and diffuse serous retinal detachments has occurred with nivolumab and ipilimumab, both with standalone and combination therapies.⁸ In another case, nivolumab was shown to cause photoreceptor loss. This was characterized on fundus autofluorescence (FAF) as areas of hypoautofluorescence and hyperautofluorescence, loss of the ellipsoid zone, and visual field constriction. Birdshot-like chorioretinopathy^9,10 and retinal vasculitis are other possible irAE with ipilimumab, pembrolizumab, atezolizumab, and durvalumab.¹¹ Mild to moderate ocular irAEs can often be treated with topical, periocular, or intravitreal steroids; however, severe irAEs may necessitate administration of systemic corticosteroids as well as either temporarily withholding or cessation of the ICI.

MEK Inhibitors

Retinal toxicities described with MEK inhibitor use include retinal vein occlusion, optic neuropathy, anterior uveitis, and panuveitis. However, the most common retinal adverse event with MEK inhibitor treatment is MEK inhibitor–associated retinopathy, which has been reported to occur in approximately 60% of patients.¹² This resembles bilateral central serous chorioretinopathy and most often occurs a few days after treatment initiation (Figure 1). Patients may experience blurred vision or sensitivity to light, though most are asymptomatic.

Even if pronounced retinopathy is present, the visual symptoms tend to be mild. Fundoscopic exam reveals subretinal fluid, which is often subfoveal but is frequently multifocal throughout the posterior pole. Retinal findings may be subtle and are often not apparent on examination alone. Optical coherence tomography (OCT) reveals a separation between the neurosensory retina and pigment epithelium with occasional small cysts in the inner retina. Increased retinal volume and central retinal thickness are dose dependent and detectable within 4 hours of drug administration and demonstrate daily fluctuation.¹³ Fluorescein angiography may show pooling at the site of subretinal fluid, although the retinal and choroidal vasculature may be normal, including on indocyanine green angiography.

In general, retinopathy tends to be transient in nature. Retinopathy typically resolves over 3 to 6 months, irrespective of whether the therapy is continued with visual acuity returning to baseline in all patients. If therapy is discontinued and later reinitiated, recurrence of exudative retinopathy is common. Follow up of surviving patients often shows normalization of OCT findings, including a normal ellipsoid zone appearance. Thus, dose reduction or temporarily discontinuing the medication could be considered, but due to the transient nature and typically mild symptoms, treatment continuation is often pursued. There is no data to support use of topical nonsteroidal anti-inflammatory drugs or dorzolamide.

BRAF Inhibitors

Commonly used BRAF inhibitors include vemurafenib (unresectable melanoma), dabrafenib (metastatic non-small cell lung cancer, anaplastic thyroid cancer, among others), and encorafenib (metastatic colorectal cancer and non-small cell lung cancer). Review of the 4 published clinical trials showed the most common ocular adverse event with vemurafenib use is uveitis (anterior uveitis, intermediate uveitis, and panuveitis), occurring in 4% of all patients.¹⁴ The uveitis is bilateral and can be successfully treated with administration of local or systemic steroids. Temporary or permanent dose reduction of the medication may be required.

Overlapping manifestations such as VKH syndrome with panuveitis, bilateral optic disc swelling, and serous retinal detachment can also occur with BRAF inhibitors. These findings typically resolve if the drug is discontinued. Rarely, serous chorioretinopathy resembling MEK inhibitor toxicity has also been reported with BRAF inhibitor use.¹⁵

Conclusion

Patients with retinopathy secondary to immunotherapy agents may be minimally symptomatic despite a dramatic appearance. Many toxicities can be successfully managed with local or systemic steroids. Although discontinuation of therapy often leads to resolution of retinopathy, it is frequently associated with recurrence of the primary tumor or new metastatic lesions. Potential benefit and harm in discontinuing the offending agent must be discussed with the treating oncologist.

William Wagner, MD, is a medical retina fellow at the Cole Eye Institute, Cleveland Clinic, in Cleveland, Ohio. He reports no relevant disclosures.

Saam Mojtahed, MD, is a resident at the Cole Eye Institute, Cleveland Clinic, in Cleveland, Ohio. He reports no relevant disclosures.

Arun D. Singh, MD, is a professor of ophthalmology and director of ophthalmic oncology at the Cole Eye Institute and Taussig Cancer Center, Cleveland Clinic. He is a scientific advisor to Aura Biosciences, a consultant to Ideaya Biosciences, and is chair of the DRCR Network’s Protocol AL study. Reach Dr. Singh at singha@ccf.org.

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