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.
- Rosner, S, Valdivia A, Hoe HJ, et al. Antibody-drug conjugates for lung cancer: payloads and progress. Am Soc Clin Oncol Educ Book. 2023:43(5);1-12. doi:10.1200/EDBK_389968
- Tolcher A, Hamilton E, Coleman RL. The evolving landscape of antibody-drug conjugates in gynecologic cancers. Cancer Treat Rev. Published online March 20, 2023. doi: 10.1016/j.ctrv.2023.102546
- Baah S, Laws M, Rahman KM. Antibody-drug conjugates-a tutorial review. Molecules. 2021;26(10):2943. doi:10.3390/molecules26102943
- Khongorzul P, Ling CJ, Khan FU, Ihsan AU, Zhang J. Antibody-drug conjugates: a comprehensive review. Mol Cancer Res. 2020;18(1):3-19. Accessed July 15, 2023. doi:10.1158/1541-7786.MCR-19-0582
- Jerjian TV, Glode AE, Thompson LA, O’Bryant CL. Antibody-drug conjugates: a clinical pharmacy perspective on an emerging cancer therapy. Pharmacotherapy. 2016;36(1):99-116. doi:10.1002/phar.1687
- Najminejad Z, Dehghani F, Mirzaei Y, et al. Clinical perspective: Antibody-drug conjugates for the treatment of HER2-positive breast cancer. Mol Ther. 2023;31(7):1874-1903. doi:10.1016/j.ymthe.2023.03.019
- Chau CH, Steeg PS, Figg WD. Antibody-drug conjugates for cancer. Lancet. 2019;394(10200):793-804. doi:10.1016/S0140-6736(19)31774-X
- Richardson DL. Ocular toxicity and mitigation strategies for antibody drug conjugates in gynecologic oncology. Gynecol Oncol Rep. 2023;46:1-2. doi:10.1016/j.gore.2023.101148
- Calo CA, O’Malley DA. Antibody-drug conjugates for the treatment of ovarian cancer. Expert Opin Biol Ther. 2021;21(7):875-887. doi:10.1080/14712598.2020.1776253.
- Tarantino P, Carmagnani Pestana R, Corti C, et al. Antibody-drug conjugates: Smart chemotherapy delivery across tumor histologies. CA Cancer J Clin. 2022;72(2):165-182. doi:10.3322/caac.21705
- Mirvetuximab soravtansine injection. Facts and Comparisons. Accessed July 28, 2023. https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/7289306.
- Elahere (mirvetuximab soravtansine) [prescribing information]. Waltham, MA: ImmunoGen; November 2022. Accessed July 8, 2023.
- Moore KN, Borghaei H, O’Malley DM, et al. Phase 1 dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor α-targeting antibody-drug conjugate, in patients with solid tumors. Cancer. 2017;123(16):3080-3087. doi:10.1002/cncr.30736
- Moore KN, Oza AM, Colombo N, et al. Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary analysis of FORWARD I. Ann Oncol. 2021;32(6):757-765. doi:10.1016/j.annonc.2021.02.017
- Matulonis UA, Birrer MJ, O’Malley DM, et al. Evaluation of prophylactic corticosteroid eye drop use in the management of corneal abnormalities induced by the antibody-drug conjugate mirvetuximab soravtansine. Clin Cancer Res. 2019;25(6):1727-1736. doi:10.1158/1078-0432.CCR-18-2474
- Tisotumab vedotin injection. Facts and Comparisons. Accessed July 28, 2023. https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/7154332#.
- Seagen Inc., & Genmab US Inc. (2022). Tivdak (tisotumab vedotin) package insert. https://www.tivdakhcp.com/resources/?gclid=CjwKCAjwzo2mBhAUEiwAf7wjkusuReXGxpUYepES8U4CxQUvuKhUouOAi8dGy7oiiLTS-ZcdFO6p_xoCnpgQAvD_BwE&gclsrc=aw.ds/prescribing information. Accessed July18, 2023.
- Tivdak (tisotumab vedotin) [prescribing information]. Bothell, WA: Seagen Inc; March 2022. Accessed July 8, 2023.
- Coleman RL, Lorusso D, Gennigens C, et al. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021;22(5):609-619. doi:10.1016/S1470-2045(21)00056-5
- de Bono JS, Concin N, Hong DS, et al. Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): a first-in-human, multicentre, phase 1-2 trial [published correction appears in Lancet Oncol. 2019;20(12):e663]. Lancet Oncol. 2019;20(3):383-393. Accessed July 28, 2023. doi:10.1016/S1470-2045(18)30859-3
- Luu K, Chu A, Chang B. A review of the novel tissue factor antibody–drug conjugate: tisotumab vedotin. J Oncol Pharm Pract. 2023;29(2):441-449. doi:10.1177/10781552221139775
- Kim SK, Ursell P, Coleman RL, Monk BJ, Vergote I. Mitigation and management strategies for ocular events associated with tisotumab vedotin. Gynecol Oncol. 2022;165(2):385-392. doi:10.1016/j.ygyno.2022.02.010
- Arn CR, Halla KJ, Gill S. Tisotumab vedotin safety and tolerability in clinical practice: managing adverse events. J Adv Pract Oncol. 2023;14(2):139-152. doi:10.6004/jadpro.2023.14.2.4
- Belantamab mafodotin injection. Facts and Comparisons. Accessed July 17, 2023. https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/6981620#ser.
- Enfortumab vedotin injection. Facts and Comparisons. Accessed July 27 2023. https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/6898069#
- Padcev (enfortumab vedotin) [prescribing information]. Northbrook, IL: Astellas Pharma US Inc; April 2023. Accessed July 8, 2023.
- Thibodeau A, Nallasamy N. Bilateral anterior subcapsular cataract development following initiation of enfortumab vedotin. Int Med Case Rep J. 2021;14:707-709. Accessed July 24, 2023. doi:10.2147/IMCRJ.S324394
- Chang E, Weinstock C, Zhang L, et al. FDA approval summary: enfortumab vedotin for locally advanced or metastatic urothelial carcinoma. Clin Cancer Res. 2021;27(4):922-927. doi:10.1158/1078-0432.CCR-20-2275
- Domínguez-Llamas S, Caro-Magdaleno M, Mataix-Albert B, Avilés-Prieto J, Romero-Barranca I, Rodríguez-de-la-Rúa E. Adverse events of antibody-drug conjugates on the ocular surface in cancer therapy. Clin Transl Oncol. 2023;10.1007/s12094-023-03261-y. doi:10.1007/s12094-023-03261-y
- Kadcyla (ado-trastuzumab) [prescribing information]. South San Francisco, CA: Genentech, Inc; April 2022. Accessed August 1, 2023.
- Burris HA, Rugo HS, Vukelja SJ, et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 2011;29(4):398-405. doi:10.1200/JCO.2010.29.5865
- Fam-trastuzumab deruxtecan injection. Facts and comparisons. Accessed July 27, 2023. https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/6899797#.
- Enhertu (fam-trastuzumab deruxtecan) [prescribing information]. Basking Ridge, NJ; Daiichi Sankyo Inc; November 2022. Accessed July 8, 2023.
- Orlandi A, Fasciani R, Cassano A, et al. Trastuzumab-induced corneal ulceration: successful no-drug treatment of a “blind” side effect in a case report. BMC Cancer. 2015;15:973. doi:10.1186/s12885-015-1969-3