The ocular toxicities observed in patients treated with antibody-drug conjugates (ADCs) have prompted the development of toxicity prevention and treatment guidelines.1-10
Severe ocular adverse events have been seen with mirvetuximab soravtansine (Elahere), a folate receptor alpha-targeted ADC approved for the treatment of folate receptor alpha-positive ovarian, fallopian tube, or peritoneal cancers in adults.
The prescribing information for mirvetuximab soravtansine has a boxed warning for ocular toxicity. 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
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Results compiled from 3 clinical trials (SORAYA, ClinicalTrials.gov Identifier: NCT04296890; FORWARD I, ClinicalTrials.gov Identifier: NCT02631876; and MIRASOL, ClinicalTrials.gov Identifier: NCT04209855) indicate that ocular adverse reactions occur in 50% to 60% of patients treated with mirvetuximab soravtansine.
The most common ocular adverse effects of mirvetuximab soravtansine include dry eye, keratopathy (corneal deposits, epithelial keratopathy, punctate keratitis), photophobia, cataract, blepharitis, blurred vision, eye pain, uveitis, and conjunctivitis.11-15
Like mirvetuximab soravtansine, tirosumab vedotin (Tivdak) has a boxed warning for ocular toxicity. Tirosumab vedotin is approved for the treatment of metastatic or recurrent cervical cancer in adults.16-18
The ocular toxicity seen with tirosumab vedotin is caused by changes in the corneal epithelium and conjunctiva.16-23 This is a predictable problem, as tisotumab vedotin targets tissue factor mechanistically, and tissue factor is expressed in the conjunctiva.16-23
Ocular toxicity has been observed in approximately 53% to 65% of patients taking tisotumab vedotin, according to findings from 2 trials (ClinicalTrials.gov Identifier: NCT02001623 and ClinicalTrials.gov Identifier: NCT03438396).
The 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. Strategies to mitigate the ocular toxicity seen with mirvetuximab soravtansine and tisotumab vedotin are outlined in Table 1.
Researchers recommend stopping treatment with 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. For other grade 3 ocular toxicities (such as conjunctival or corneal scarring) both ADCs may need to be permanently discontinued. Patients should discontinue mirvetuximab soravtansine and tirosumab vedotin in the event of any grade 4 ocular toxicities.11-23
Less Severe Ocular Adverse Effects
Enfortumab vedotin (Padcev) is approved for the treatment of advanced or metastatic urothelial cancer in adults.24,25 It is known to cause ocular adverse events in approximately 46% of patients, and these events can occur at any time.24-27
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.24-28 In general, patients should be counseled to report any ocular symptoms, and artificial tears are recommended by some investigators.
Ocular side effects have also been reported in patients taking ado-trastuzumab emtansine (T-DM1; Kadcyla) and those taking fam-trastuzumab deruxtecan (Enhertu).29-33
T-DM1 is approved as adjuvant treatment for HER2-positive early breast cancer in patients with residual invasive disease following neoadjuvant taxane and trastuzumab-based treatment.29,30 Fam-trastuzumab deruxtecan is approved for the treatment of unresectable or metastatic breast, gastric, or non-small cell lung cancers in adults.31-33
The ocular side effects associated with T-DM1 and fam-trastuzumab deruxtecan include conjunctivitis, dry eyes, increased lacrimation, and some blurred vision.29-33
Overall, most ocular adverse events related to ADCs are manageable with appropriate baseline and periodic evaluations and implementation of mitigation strategies. Ophthalmology consultations may be necessary in patients with cases of severe or persistent issues, and dose reductions or discontinuation of ADCs may be required in cases where patients are not responding to appropriate interventions for severe ocular toxicities.
References
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2. 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
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7. 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
8. 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
9. 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
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11. Mirvetuximab soravtansine injection. Facts and Comparisons. Accessed July 28, 2023. https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/7289306.
12. Elahere (mirvetuximab soravtansine). Prescribing information. Waltham, MA: ImmunoGen; November 2022. Accessed July 8, 2023.
13. 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
14. 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
15. 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
16. Tisotumab vedotin injection. Facts and Comparisons. Accessed July 28, 2023. https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/7154332#.
17. 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 July 18, 2023.
18. Tivdak (tisotumab vedotin). Prescribing information. Bothell, WA: Seagen Inc; March 2022. Accessed July 8, 2023.
19. 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
20. 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
21. 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
22. 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
23. 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
24. Enfortumab vedotin injection. Facts and Comparisons. Accessed July 27 2023. https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/6898069#
25. Padcev (enfortumab vedotin). Prescribing information. Northbrook, IL: Astellas Pharma US Inc; April 2023. Accessed July 8, 2023.
26. 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
27. 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
28. 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
29. Kadcyla (ado-trastuzumab). Prescribing information. South San Francisco, CA: Genentech, Inc; April 2022. Accessed August 1, 2023.
30. 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
31. Fam-trastuzumab deruxtecan injection. Facts and comparisons. Accessed July 27, 2023. https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/6899797#.
32. Enhertu (fam-trastuzumab deruxtecan). Prescribing information. Basking Ridge, NJ; Daiichi Sankyo Inc; November 2022. Accessed July 8, 2023.
33. 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
This article originally appeared on Ophthalmology Advisor
