Recommendations, key points and references

ADCs are a valuable therapeutic option for many cancers and are likely to be used with increasing frequency in the future. Although they are designed to minimise systemic toxicity due to off-target effects, some of these therapies are associated with ocular adverse events.

15.1. Recommendations for clinical practice

1. Recognise moderate acuity loss or blurred vision as an early warning symptom. Moderate loss of visual acuity or blurred vision may be an early symptom of ADC-related ocular adverse events, and ophthalmologic examination for persistent or worsening symptoms during treatment is advisable to decipher the nature and severity of these events as early as possible.
2. Modify dosing collaboratively. In the case of moderate loss of visual acuity as a symptom of ADC-related corneal adverse events, oncologists should consider dose modification — reduction or delay — and, in collaboration with ophthalmologists, the use of ocular topical treatments to manage ocular symptoms.
3. Refer before initiation where feasible. In line with ADC-specific guidance, referral for ophthalmologic assessment should be considered before the start of treatment. Where access is limited, referral when ocular symptoms develop or worsen may be sufficient to differentiate ADC-related events from those of other causes.
4. Organise a rapid-access network. Patients with ADC-related ocular adverse events should be seen within a few days of the occurrence of the event. Ideally, organising a network of ophthalmologists and other eye care professionals who would be available as needed for these patients would help address ocular issues in a timely manner.
5. Do not generalise protocols. Although the product labelling for certain approved ADCs includes guidance regarding dose modification for managing ocular adverse events, these recommendations are specific to the individual ADC agent, and labelling for other ADCs does not clearly specify what other ophthalmologic treatments should be used in conjunction with these dose modifications.

15.2. Unmet needs

There are limited data concerning the effectiveness of the strategies implemented to minimise and mitigate these ocular adverse events, emphasising the need for the involvement of eye-care providers in the network of anti-cancer drug prescribers, especially for patients receiving ADC-based treatment.

Unfortunately, access to ophthalmologists³⁹ remains a global issue, especially among lower- and middle-income populations, with multiple barriers contributing to this suboptimal access, including approachability, acceptability, affordability and availability. Improving access to ophthalmology care is crucial for patients with ADC-related ocular adverse events.

Identifiable unmet needs to date are the following:

• A consensus definition of phenotypes. The terms "keratopathy", "keratitis", "corneal disorder" and "epithelial changes" are used non-uniformly in trials, which makes incidences hard to compare.
• Grading criteria adapted to the actual semiology. Current CTCAE scales, based mainly on visual acuity, are poorly adapted to a keratopathy that begins peripherally without visual impact.
• Prospective prophylaxis data. The contradictory results observed for topical corticosteroids call for dedicated trials, agent by agent, with primary ophthalmic endpoints.
• Characterisation of LSCD risk. The question of reversibility of limbal niche damage governs long-term functional prognosis and has not been studied.
• Mechanistic mitigation strategies. Pharmacological modulation of macropinocytosis and reduction of positive charges on ADCs are the only approaches currently capable of acting on the cause rather than the consequence.
• Benefit–risk assessment integrating survival data. Real-world analyses showing rapid progression after permanent discontinuation require the oncologic cost of stopping to be built into any ophthalmic recommendation.

15.3. Conclusion

In this setting, ophthalmologists play an essential role in the detection, mitigation and management of these ocular adverse events. They have an important role to play in careful adherence to recommended eye care and the administration of appropriate treatments when ocular adverse events occur, to limit sequelae. Improved specialised follow-up is advised when increased frequency and intensity of specific ADC therapies' ocular adverse events are reported.

ADC ocular toxicity illustrates a situation in which ophthalmic competence directly governs the conduct of a systemic treatment. Mastering it rests on three simple elements: identify the phenotype before scoring it, know the guidance specific to the agent being administered, and rapidly communicate an actionable conclusion to the oncologist.

Key points

1. The majority of ADC-related ocular adverse events are attributed to off-target toxicity: linker instability and deconjugation, Fc receptor-mediated uptake, nonspecific endocytosis via macro- and micropinocytosis, and the bystander effect. On-target toxicity exists — HER2, MUC16, tissue factor — but is not the dominant mechanism.
2. The limbus concentrates four vulnerability factors: an actively dividing progenitor niche, a terminal vascular arcade, constitutively pinocytotic immune cells and a high nerve density. The peripheral-then-centripetal topography of lesions follows from this.
3. Three distinct corneal phenotypes are identified: microcyst-like epithelial change keratopathy, superficial punctate keratitis and keratoconjunctivitis, and limbal stem cell deficiency suggested by hurricane keratopathy.
4. Refraction is a diagnostic instrument: hyperopic shift for peripheral MECs, myopic shift for paracentral or central MECs. A myopic shift should be considered a warning sign of central migration.
5. Best-corrected visual acuity is not reliable at the early stage, since microcysts begin peripherally without visual impact. Slit lamp and refraction precede CTCAE grading.
6. Corneal nerve toxicity, documented with belantamab mafodotin and depatuxizumab mafodotin, leads to hypoaesthesia, reduced lacrimal reflex and epithelial turnover, and may progress to neurotrophic keratopathy with risk of persistent epithelial defect or perforation.
7. Prophylaxis is ADC-specific and does not generalise: topical corticosteroids reduced conjunctivitis with tisotumab vedotin but were ineffective in DREAMM-2 with belantamab mafodotin, in a within-patient controlled protocol.
8. The majority of events are grade 1–2 and reversible with supportive care and dose modification. Permanent discontinuation carries a documented oncologic cost: 70 % progression at a median of 3 months in one series, and progression-free survival of 10 versus 4 months according to whether treatment was restarted or permanently stopped.
9. Rapid access to an ophthalmologist — within a few days of the event — is the limiting organisational factor. Establishing a dedicated network is a practical recommendation of the article.
10. In a patient with corneal hypoaesthesia and impaired epithelial renewal, topical NSAIDs carry a risk of stromal melt and should be avoided.

References

1. Gabison EE, Chastang P, Menashi S, Mourah S, Doan S, Oster M, Mauviel A, Hoang-Xuan T. Late corneal perforation after photorefractive keratectomy associated with topical diclofenac: involvement of matrix metalloproteinases. Ophthalmology. 2003;110(8):1626-1631.
2. Gabison EE, Huet E, Baudouin C, Menashi S. Direct epithelial-stromal interaction in corneal wound healing: role of EMMPRIN/CD147 in MMPs induction and beyond. Prog Retin Eye Res. 2009;28(1):19-33.
3. Bourdin A, Gournay V, Doan S, Prata PH, Kaphan E, Michonneau D, Socié G, Peffault de Latour R, Gabison EE. Severe corneal manifestations of graft-versus-host disease: experience of a tertiary referral center. Ocul Surf. 2025;36:19-24. PMID 39709126.
4. Rousseau A, Michot JM, Labetoulle M. Belantamab mafodotin-induced epithelial keratopathy masquerading myopic surgery. Ophthalmology. 2020;127(12):1626.
5. Mahalingaiah PK, et al. Potential mechanisms of target-independent uptake and toxicity of antibody-drug conjugates. Pharmacol Ther. 2019;200:110-125.
6. Domínguez-Llamas S, Caro-Magdaleno M, Mataix-Albert B, et al. Adverse events of antibody-drug conjugates on the ocular surface in cancer therapy. Clin Transl Oncol. 2023;25:3086-3100.
7. Eaton JS, Miller PE, Mannis MJ, Murphy CJ. Ocular adverse events associated with antibody-drug conjugates in human clinical trials. J Ocul Pharmacol Ther. 2015;31(10):589-604.
8. Farooq AV, et al. Corneal epithelial findings in patients with multiple myeloma treated with antibody-drug conjugate belantamab mafodotin. Ophthalmol Ther. 2020;9(4):889-911.
9. Fortes BH, Tailor PD, Dalvin LA. Ocular toxicity of targeted anticancer agents. Drugs. 2021;81(7):771-823.
10. Aschauer J, Donner R, Lammer J, Roberts P, Funk M, Agis H, Schmidinger G. Corneal toxicity associated with belantamab mafodotin is not restricted to the epithelium: neuropathy studied with confocal microscopy. Am J Ophthalmol. 2022;242:116-124.
11. Canestraro J, et al. Refractive shifts and changes in corneal curvature associated with antibody-drug conjugates. Cornea. 2022;41(7):792-801.
12. Bui AD, Lopez S, Seitzman GD. Chemotherapy-induced hyperopic surprise in a woman with multiple myeloma. JAMA Ophthalmol. 2022;140(9):e223226.
13. Lonial S, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21(2):207-221.
14. Lonial S, Nooka AK, Thulasi P, et al. Management of belantamab mafodotin-associated corneal events in patients with relapsed or refractory multiple myeloma (RRMM). Blood Cancer J. 2021;11:103.
15. Abeykoon JP, et al. Impact of belantamab mafodotin-induced ocular toxicity on outcomes of patients with advanced multiple myeloma. Br J Haematol. 2022;199(1):95-99.
16. Mohan M, et al. Belantamab mafodotin ocular toxicity and treatment interruption in relapsed refractory multiple myeloma. 2022.
17. de Bono JS, et al. Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): a first-in-human, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(3):383-393.
18. Coleman RL, et al. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6). Lancet Oncol. 2021;22(5):609-619.
19. 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. PMID 35277279.
20. Parikh AA, Hanna J, Shah AP. Acute keratoconjunctivitis associated with tisotumab vedotin-tftv for metastatic cervical cancer. Am J Ophthalmol Case Rep. 2024;33:101979. PMID 38230392.
21. Gazzah A, Bedard PL, Hierro C, et al. Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody-drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study. Ann Oncol. 2022;33(4):416-425.
22. Ricordel C, et al. Tusamitamab ravtansine chez les patients atteints de CBNPC non épidermoïde CEACAM5-positif : exposition prolongée et événements cornéens. 2022. [communication de congrès — référence à consolider]
23. 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. PMID 30413525.
24. 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.
25. Boni V, et al. Praluzatamab ravtansine, a CD166-targeting antibody-drug conjugate, in patients with advanced solid tumors: an open-label phase I/II trial. Clin Cancer Res. 2022;28(10):2020-2029.
26. Banerji U, et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 2019;20(8):1124-1135.
27. Santin AD, et al. Safety and activity of anti-mesothelin antibody-drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study. Int J Gynecol Cancer. 2023.
28. Beeram M, et al. A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced HER2-positive breast cancer. Cancer. 2012;118(23):5733-5740.
29. Zhao H, et al. Modulation of macropinocytosis-mediated internalization decreases ocular toxicity of antibody-drug conjugates. Cancer Res. 2018;78(8):2115-2126.
30. Best RL, et al. Microtubule and tubulin binding and regulation of microtubule dynamics by the antibody drug conjugate (ADC) payload, monomethyl auristatin E (MMAE). Toxicol Appl Pharmacol. 2021;421:115534.
31. Brachet G, et al. Increment in drug loading on an antibody-drug conjugate increases its binding to the human neonatal Fc receptor in vitro. Mol Pharm. 2016;13(4):1405-1412.
32. Frutos-Rincón L, Gómez-Sánchez JA, Íñigo-Portugués A, Acosta MC, Gallar J. An experimental model of neuro-immune interactions in the eye: corneal sensory nerves and resident dendritic cells. Int J Mol Sci. 2022;23(6):2997.
33. Blalock TD, et al. Functions of MUC16 in corneal epithelial cells. Invest Ophthalmol Vis Sci. 2007;48(10):4509-4518.
34. Ando R, et al. Tissue factor expression in human pterygium. Mol Vis. 2011;17:63-69.
35. Beck A, Goetsch L, Dumontet C, Corvaïa N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16(5):315-337.
36. Mangione CM, et al. Development of the 25-item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol. 2001;119(7):1050-1058.
37. Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol. 2000;118(5):615-621.
38. Popat R, et al. DREAMM-2 : effets du bélantamab mafodotine sur les mesures rapportées par le patient. Blood. 2020;136(Suppl 1):27-28. [résumé de congrès — publications in extenso : PMID 37808071 et PMID 38144529]
39. Marmamula S, et al. Obstacles au recours aux soins oculaires après orientation. Br J Ophthalmol. 2023. [référence à préciser]
40. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Publié le 27 novembre 2017.
41. Dimopoulos MA, Hungria VTM, Radinoff A, et al. Efficacy and safety of single-agent belantamab mafodotin versus pomalidomide plus low-dose dexamethasone in relapsed or refractory multiple myeloma (DREAMM-3): a phase 3, open-label, randomised study. Lancet Haematol. 2023;10:e801-e812. PMID 37793771.
42. Hungria V, Robak P, Hus M, et al. Belantamab mafodotin, bortezomib, and dexamethasone for multiple myeloma (DREAMM-7). N Engl J Med. 2024;391(5):393-407. PMID 38828933.
43. Dimopoulos MA, Beksac M, Pour L, et al. Belantamab mafodotin, pomalidomide, and dexamethasone in multiple myeloma (DREAMM-8). N Engl J Med. 2024;391(5):408-421. doi:10.1056/NEJMoa2403407.
44. Belantamab mafodotin plus bortezomib and dexamethasone in relapsed or refractory multiple myeloma (DREAMM-7): updated overall survival analysis. Lancet Oncol. 2025. PMID 40680754.
45. The clinical journey of belantamab mafodotin in relapsed or refractory multiple myeloma: lessons in drug development. Blood Cancer J. 2025;15:15.
46. U.S. Food and Drug Administration. Oncologic Drugs Advisory Committee, réunion du 17 juillet 2025 — document de synthèse et votes sur les associations à base de bélantamab mafodotine.
47. U.S. Food and Drug Administration. Blenrep (belantamab mafodotin-blmf) approval history : approbation accélérée le 5 août 2020 ; révocation de la licence le 20 mars 2023 ; approbation en association au bortézomib et à la dexaméthasone le 23 octobre 2025.
48. Sanofi. Communiqué du 21 décembre 2023 : arrêt du programme de développement du tusamitamab ravtansine après l'essai de phase 3 CARMEN-LC03.
49. Commission européenne. Autorisation de mise sur le marché d'Elahere (mirvétuximab soravtansine) dans l'Union européenne, 18 novembre 2024.
50. U.S. Food and Drug Administration. Datroway (datopotamab deruxtecan-dlnk) approval history : 17 janvier 2025 (sein HR+/HER2−) ; 22 mai 2026 (sein triple négatif).