Highlights
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Trastuzumab botidotin induces vision-threatening corneal epitheliopathy.
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Pseudomicrocysts and vortex keratopathy characterize the corneal epitheliopathy.
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In vivo confocal microscopy reveals subbasal nerve thinning and density reduction.
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Decreased Schirmer values along with reduced TMH and shortened TBUT suggest dry eye.
Purpose
HER2-targeted antibody-drug conjugates (ADCs) demonstrate significant efficacy in HER2-mutated or HER2-positive tumors but may cause ocular adverse events (AEs), particularly corneal epitheliopathy and blurred vision. This study aimed to characterize the clinical features of trastuzumab botidotin (a HER2-targeted ADC)-related corneal AEs.
Design
Retrospective case series.
Subjects
Eight adult patients (15 eyes) with HER2-mutated or HER2-positive solid tumors treated with trastuzumab botidotin.
Methods
Assessments included best-corrected visual acuity, Ocular Surface Disease Index, Schirmer’s test, tear break-up time, tear meniscus height, and corneal fluorescein staining. In vivo confocal microscopy (IVCM) was performed to evaluate cellular structures and confirm lesion characteristics.
Main Outcome Measures
Corneal AEs associated with trastuzumab botidotin and their clinical features.
Results
Corneal AEs occurred in all eight patients. The mean time to visual impairment onset was 37.25 ± 5.90 days after trastuzumab botidotin initiation, with symptom severity peaking at 82.75 ± 14.26 days. Ocular Surface Disease Index scores increased from 5.73 ± 2.67 at baseline to 65.10 ± 13.26 at peak severity. Trastuzumab botidotin caused dry eye in all patients ( n = 8), resulting in reduced Schirmer’s test results (from 8.94 ± 1.66 mm to 4.20 ± 1.58 mm), shortened tear break-up time (from 9.63 ± 1.21 seconds to 3.37 ± 1.61 seconds), and decreased tear meniscus height (from 0.23 ± 0.04 mm to 0.14 ± 0.02 mm). Slit-lamp microscopy and fluorescein staining revealed that trastuzumab botidotin induced distinct corneal epitheliopathy, characterized by pseudomicrocysts, punctate epitheliopathy, diffuse punctate epitheliopathy, and vortex keratopathy. IVCM correlated these findings, showing cyst-like hyperreflective structures in the superficial epithelium, grape-like hyperreflective clusters in wing cells and basal cells, and associated cellular disorganization. IVCM demonstrated neurotoxic damage, characterized by thinning of subbasal nerves, decreased nerve density, and focal discontinuities in the subbasal nerve plexus.
Conclusions
Trastuzumab botidotin was associated with visual impairment, corneal epitheliopathy, and nerve damage. Close collaboration between ophthalmologists and oncologists is crucial for early detection of corneal AEs related to ADC therapy, thereby improving clinical outcomes and patient quality of life.
INTRODUCTION
H uman epidermal growth factor receptor 2 (HER2) is a member of the HER tyrosine kinase family, which includes epidermal growth factor receptor (HER1/erbB1), HER2 (erbB2/HER2/neu), HER3 (erbB3), and HER4 (erbB4). HER2 is distinguished by its lack of intrinsic inhibition or physiological ligands, with its extracellular domain constitutively primed for dimerization. The elevated expression of HER2 protein, resulting from either gene amplification or dysregulated transcription mechanisms, has been well-documented in many studies. HER2 is expressed on the cell membrane of epithelial cells throughout multiple organ systems, including the gastrointestinal, respiratory, reproductive, and urinary tracts, as well as in the skin, breast, and placenta. This field urgently requires groundbreaking agents. Antibody-drug conjugates (ADCs) are targeted therapeutic agents composed of three principal components, a tumor-targeting monoclonal antibody linked via a linker to a cytotoxic payload. These constructs integrate the selective binding properties of antibodies with the cell-killing capability of cytotoxic payloads.
As a novel class of targeted therapeutic agents, ADCs demonstrate significant improvement in therapeutic efficacy of monoclonal antibodies. However, there is also growing reports of ocular adverse events (AEs) induced by ADCs. Corneal epitheliopathy, blurred vision, and dry eye disease were the most frequently reported ocular AEs in clinical trials of ADCs. Belantamab mafodotin was reported to cause keratopathy in 72% of patients, and blurred vision in 18%. Mirvetuximab soravtansine was reported to cause keratopathy in 32% of patients and visual acuity loss in 41%. Tisotumab vedotin was reported to cause dry eye in 23%.
Trastuzumab botidotin (A166) is a HER2-targeted ADC composed of a humanized anti-HER2 monoclonal antibody site-specifically conjugated via a stable protease-cleavable valine citrulline linker to Duostatin-5, a potent microtubule-disrupting cytotoxic payload. Trastuzumab botidotin has been approved for marketing in China by the National Medical Products Administration (NMPA) on October 17, 2025, for the treatment of HER2-positive breast cancer. In the Phase I clinical study, treatment-related AEs (TRAEs) were systematically evaluated, with ocular AEs emerging as the most predominant manifestations. The most frequent TRAEs of any grade included corneal epitheliopathy (84.0%), blurred vision (74.1%), and dry eye (32.1%). These findings indicate that close monitoring of ocular safety is necessary in patients receiving trastuzumab botidotin. However, adequate details regarding the clinical characteristics of these ocular TRAEs were lacking. This study aimed to characterize the ocular TRAEs of trastuzumab botidotin in patients with advanced HER2-mutated or HER2-positive solid tumors.
MATERIALS AND METHODS
ethics
This retrospective study enrolled 8 adult patients (15 eyes, including one monocular individual) with HER2-mutated or HER2-positive solid tumors who received trastuzumab botidotin treatment between November 2021 and June 2023. Study adhered to the ethical principles of the Declaration of Helsinki and was approved by the Ethics Committee of The Second Affiliated Hospital of Harbin Medical University.
study design
Eligible patients had histologically confirmed HER2-mutated or HER2-positive solid tumors and were receiving trastuzumab botidotin. Exclusion criteria included: (1) A history of ocular surgery or trauma. (2) Active or unstable corneal diseases or severe dry eye. (3) Use of contact lenses within 4 weeks prior to enrollment. (4) Grade ≥2 peripheral sensory neuropathy according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Patients received trastuzumab botidotin at 4.8 mg/kg via intravenous infusion every 3 weeks. Ocular monitoring was performed at baseline (pretreatment) and every 3 weeks per treatment cycle, with additional evaluations conducted as needed for any ocular AEs that emerged.
assessments and signs
Best-corrected visual acuity (BCVA) was assessed using the Snellen chart. The Ocular Surface Disease Index (OSDI) is a widely used questionnaire, which consists of 12 questions assessing the frequency of symptoms, environmental triggers, and vision-related quality of life. Dry eye-related measurements included nonanesthetized Schirmer’s test (performed with standardized paper strips; moistened strip length was measured after 5 minutes), tear break-up time (TBUT), and tear meniscus height (TMH). Anterior segment photography (performed using a MediWorks digital slit-lamp camera) combined with corneal fluorescein staining was used to evaluate corneal lesions. In vivo confocal microscopy (IVCM; Heidelberg Retina Tomograph III system with a 63 × lens, 400 × 400 µm scan field, Heidelberg Engineering) was additionally performed to assess corneal cellular structures and confirm lesion characteristics if corneal AEs occur.
grading criteria
The grading of visual acuity loss and corneal AEs in this study followed the multicenter, interdisciplinary consensus guidelines for ocular AEs associated with experimental oncology drugs. This standardized scale was specifically developed to evaluate visual acuity loss, corneal changes, and other ocular AEs induced by experimental oncology drugs. The severity of trastuzumab botidotin-related dry eye was graded using the Tear Film and Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II) diagnostic criteria and classification system, which integrates assessments of OSDI, tear film stability, and tear volume. ,
data collection
Descriptive data were recorded as mean ± standard deviation (SD). BCVA, Schirmer’s test, TBUT, and TMH were reported and analyzed in the more affected eye (defined as the eye with greater BCVA decline at the initial onset of AE) of each patient to better reflect clinical burden and avoid underestimating treatment-related ocular AEs. The monocular patient was analyzed using the existing eye.
RESULTS
This study included 8 patients (15 affected eyes) with histologically confirmed HER2-mutated or HER2-positive solid tumors who received trastuzumab botidotin. The mean age of the patients was 61.5 ± 11.4 years (range, 44-74 years). Table 1 summarizes the ocular AEs characteristics among all study patients. AEs occurred at a mean onset of 37.25 ± 5.90 days postbaseline (range, 27-45 days), with peak severity (worst observed values) occurring at a mean of 82.75 ± 14.26 days (range, 63-108 days). Table 2 summarized the AEs manifestations and severity grading among enrolled patients. All patients ( n = 8) experienced visual acuity loss, with 25% classified as Grade 1 ( n = 2), 37.5% as Grade 2 ( n = 3), and another 37.5% as Grade 3 ( n = 3). And all patients ( n = 8) developed dry eye, which was exclusively Grade 3 in severity. Corneal AEs affected all patients, manifesting as Grade 1 (37.5%, n = 3) or Grade 2 (62.5%, n = 5) events. The graded corneal AEs included punctate epitheliopathy (3 patients, 6 of 15 eyes; all Grade 1), diffuse epitheliopathy (2 patients, 3 of 15 eyes; all Grade 2), and vortex keratopathy (4 patients, 6 of 15 eyes; all Grade 2). No Grade 4 events were observed during the follow-up period.
TABLE 1
Ocular AEs Characteristics of Eight Patients.
| Sex | Age | AEs Observed (D) | BCVA | OSDI Score | Schirmer’s Test (mm/5 Min) | TBUT (s) | TMH (mm) | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Onset | WOV | BL | WOV | BL | WOV | BL | WOV | BL | WOV | BL | WOV | |||
| #1 | F | 60 | 27 | 108 | 20/25 | 20/80 | 8.33 | 85.42 | 8.7 | 2.0 | 10.14 | 2.55 | 0.18 | 0.10 |
| #2 | F | 74 | 38 | 77 | 20/25 | 20/80 | 6.25 | 68.75 | 6.9 | 3.7 | 9.45 | 2.32 | 0.26 | 0.15 |
| #3 | F | 44 | 31 | 89 | 20/25 | 20/40 | 2.08 | 72.92 | 9.2 | 2.8 | 11.39 | 2.34 | 0.23 | 0.14 |
| #4 | M | 62 | 36 | 77 | 20/25 | 20/30 | 4.17 | 50.00 | 9.7 | 6.3 | 10.82 | 5.90 | 0.27 | 0.13 |
| #5 | M | 45 | 42 | 84 | 20/20 | 20/30 | 4.17 | 45.83 | 12.4 | 5.3 | 9.38 | 1.91 | 0.20 | 0.17 |
| #6 | M | 71 | 45 | 63 | 20/30 | 20/63 | 10.42 | 75.00 | 7.5 | 2.9 | 8.47 | 4.16 | 0.21 | 0.18 |
| #7 | M | 69 | 41 | 70 | 20/30 | 20/50 | 6.25 | 58.33 | 8.3 | 5.9 | 7.63 | 5.56 | 0.17 | 0.14 |
| #8 | F | 67 | 38 | 94 | 20/25 | 20/80 | 4.17 | 64.58 | 8.8 | 4.7 | 9.74 | 2.23 | 0.29 | 0.13 |
| M ± SD | – | 61.5 ± 11.4 | 37.25 ± 5.90 | 82.75 ± 14.26 | – | – | 5.73 ± 2.67 | 65.10 ± 13.26 | 8.94 ± 1.66 | 4.20 ± 1.58 | 9.63 ± 1.21 | 3.37 ± 1.61 | 0.23 ± 0.04 | 0.14 ± 0.02 |
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