Antibody-Drug Conjugate Therapies Carry Potential for Severe Adverse Ocular Effects

Biotechnology continues to provide drug compounds that offer many new options for patients suffering with a variety of cancers, including hematologic and solid tumor. In general, these biologic antibody-drug conjugates (ADCs) show improved efficacy and toxicity data when they are compared with standard chemotherapy, as these agents are more targeted and specific for the cancer types that they treat. 

However, traditional chemotherapeutic agents are less selective against cancer cells which contributes to their many systemic adverse effects, including those that affect the eye.^1-8 

Antibody-Drug Conjugate Basics

The biochemistry behind antibody-drug conjugates, also called “biomarker-directed therapy,” provides a straightforward way to understand exactly how these monoclonal antibodies (mABs) work. Antibody-drug conjugates are made up of 3 distinct parts: The antibody, the linker, and the cytotoxic payload (also called, the warhead).  The antibody portion comes from the immunoglobulin G (IgG) class in ADCs. The linker connects the antibody to the cytotoxic payload. Additionally, the linker helps maintain the stability of the ADC until it reaches the targeted antigen/tumor cells, where the linker then releases the cytotoxic agent. The cytotoxic payload portion is responsible for the cytotoxic effects of the ADC on target tumor cells after it has been delivered and released by the linker. 

The endpoint of the antibody+linker+cytotoxic agent is the delivery of a highly selective and concentrated cytotoxic payload via an antibody-mediated mechanism, resulting in increased death of antigen target cancer cells, while sparing healthy cells. Variability in antibody-drug conjugate designs and structures results in differences in the pharmacokinetics and pharmacodynamics between agents, with resultant differences in efficacy and toxicity profiles. Researchers have observed that ADCs with a wide variety of targets have the ability to  cause ocular toxicity, and most of those are not known to be expressed in the cornea (except human epidermal growth factor receptor 2 [HER2]). This indicates that the ADCs produce side effects and toxicities in nontargeted cells and tissues. The on-target and nontargeted reversible and irreversible ocular toxicities have resulted in the development of toxicity prevention and treatment guidelines for ophthalmologists, which simplifies the care of patients undergoing treatment with a ADC with ocular side effects and toxicities.^1-10

Potential Severe Ocular Toxicities

Mirvetuximab soravtansine injection (Elahere, Immunogen) is approved for the treatment of folate receptor-alpha positive ovarian, fallopian tube, or peritoneal cancers in adult patients, and it is a folate receptor alpha targeted antibody-drug conjugate. It has a boxed warning for ocular toxicity, and the potential for toxicity is considered to be caused by off-target effects on the cornea, as folate receptor alpha expression is not found in human corneal tissue.^11-13  Results compiled from 3 clinical trials (the SORAYA trial, ClinicalTrials.gov Identifier: NCT04296890; the FORWARD I trial, ClinicalTrials.gov Identifier: NCT02631876; and the MIRASOL trial, ClinicalTrials.gov Identifier: NCT04209855) indicate that ocular adverse reactions occur in 50% to 60% of patients. 

The most commonly experienced adverse effects include dry eye, keratopathy (corneal deposits, epithelial keratopathy, punctate keratitis), photophobia, cataract, blepharitis, blurred vision, eye pain, uveitis and conjunctivitis.^11-15

Tirosumab vedotin injection (Tivdak, SEAGEN) is approved for the treatment of metastatic or recurrent cervical cancer in adult patients.^16-18 Like mirvetuximab soravtansine, tisotumab vedotin also has a boxed warning for ocular toxicity that is caused by changes in the corneal epithelium and conjunctiva, which may result in toxicities.^16-23 This is a predictable problem as tisotumab vedotin targets tissue factor mechanistically, and tissue factor is expressed in the conjunctiva.^16-23 These adverse effects have been observed in approximately 53% to 65% of patients taking tisotumab vedotin, acording to findings from the Tisotumab Vedotin Antibody-Drug Conjugate (HuMax^®-TF-ADC) Safety Study in Patients With Solid Tumors clinical trial (ClinicalTrials.gov Identifier: NCT02001623) and the Trial of Tisotumab Vedotin in Cervical Cancer (ClinicalTrials.gov Identifier: NCT03438396)

Adverse effects include severe vision loss and corneal ulceration, typically occurring in the first few months of treatment.^16-23 However, most patients in those 2 trials experienced conjunctival inflammation and more mild ocular adverse effects, such as dry eye, conjunctivitis, blepharitis, and keratitis. 

The boxed warnings from the FDA as well as clinical trials and practice anecdotes for mirvetuximab soravtansine and tisotumab vedotin are outlined in Table 1. 

Adjustments in Therapy

Researchers recommend ceasing mirvetuximab soravtansine and tirosumab vedotin in the event of grade 2 ocular toxicities until improvement is seen, and then resuming treatment at the same dosage. For some grade 3 ocular toxicities (such as moderate uveitis), tirosumab vedotin and mirvetuximab soravtansine can be stopped until improvement is seen, and then restarted at a reduced dose. In other grade 3 ocular toxicities (such as conjunctival or corneal scarring) both antibody-drug conjugate agents may need to be permanently discontinued. Patients should discontinue mirvetuximab soravtansine and tirosumab vedotin for any grade 4 ocular toxicities.^11-23

Belantamab mafodotin injection (Blenreb, GSK) was approved for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies. However the confirmatory randomized DREAMM-3 phase 3 trial (ClinicalTrials.gov Identifier: NCT04162210) did not meet the primary end point of superior progression-free survival, so the Blenrep biologic license was withdrawn by the FDA on February 6, 2023. 

Patients who are currently using the drug with clinical benefits will continue to have access to Blenrep through a GlaxoSmithKline compassionate use program, but new patients will not have access to the drug.²⁴

Less Severe Ocular Adverse Effects

Enfortumab vedotin injection (Padcev, Seattle Genetics) is approved for the treatment of advanced or metastatic urothelial cancer in adult patients.^25,26 It is known to cause ocular adverse effects in approximately 46% of patients, and can occur at any time.^25-28 The most common side effects involve the cornea, and include keratitis, blepharitis, conjunctivitis, blurred vision, and dry eye syndrome. Cases of bilateral anterior subcapsular cataracts have also been reported in a small number of patients.^25-29 In general, patients should be counseled to report any ocular symptoms, and artificial tears are recommended by some investigators. ^25-29 

Ado-trastuzumab emtansine (T-DM1) (Kadcyla, Genentech) is approved as adjuvant treatment of HER2-positive early breast cancer in patients with residual invasive disease following neoadjuvant taxane and trastuzumab-based treatment.^30,31 Fam-trastuzumab deruxtecan injection (Enhertu, SANKYO) is approved for the treatment of unresectable or metastatic breast, gastric, or non-small cell lung cancers in adults.^32-34 Ocular side effects, while generally mild, have been reported in patients taking both agents, and may include conjunctivitis, dry eyes, increased lacrimation, and some blurred vision.^30-34 (Clinicaltrials.gov Identifier: NCT00288002)

Antibody-drug conjugates as a group, are some of the most sophisticated pharmaceutical agents available in all of pharmacology. They play an important role in hematologic and solid tumor cancers, including metastatic and recurrent cancers where no other treatment options exist. While ocular adverse reactions may occur with some ADCs, most of these reactions are generally manageable with appropriate baseline and periodic evaluations and implementation of mitigation strategies. In general, antibody-drug conjugates have excellent risk-to-benefit ratios, however, ophthalmology consultations may be necessary in patients with cases of severe or persistent issues, and dose reduction or discontinuation of the ADC may be required in cases where patients are not responding to appropriate interventions for severe ocular toxicities.