Table 1.
Summary of Features of Ocular and/or Vision-Impairing AEs Associated with Administration of Antibody–Drug Conjugates
| ADC | Indication (neoplasm) | Target antigen/cytotoxin/linker | Toxicity/symptom | Incidence | Gradea | Outcome | Reference |
|---|---|---|---|---|---|---|---|
| IMGN242 (huC242-DM4) | CanAg-expressing solid tumors | CanAg/DM4/SPDB | Decreased visual acuity, corneal deposits, keratitis | 2/30 (during second treatment cycle, at 223 mg/m2) | Not specified | Resolved in 1 patient; significantly improved in the other | Mita et al.18 |
| IMGN242 (huC242-DM4) | CanAg-positive gastric or gastroesophageal junction tumors | CanAg/DM4/SPDB | Not specified | 3/6 (receiving 168 mg/m2) | Not specified | Not specified | Goff et al.19 |
| Trastuzumab emtansine (T-DM1) | Advanced HER2+ breast cancer | HER2/DM1/SMCC | Conjunctivitis, photophobia, swollen tear duct | 1/24b | Grade 1–2 | Not specified | Krop et al.26 |
| Trastuzumab emtansine (T-DM1) | HER2+ breast cancer | HER2/DM1/SMCC | Dry eye, increased lacrimation, vision blurred/vision impairment, conjunctivitisc | 35/112 | 1–2c | Not specified | Burris et al.27 |
| Trastuzumab emtansine (T-DM1) | Advanced HER2+ breast cancer | HER2/DM1/SMCC | Cataract, ocular surface disease, punctuate keratitis, dry eye | 13/28 | 3 (2 patients); others not specified | Not specified | Beeram et al.28 |
| SAR3419 (huB4-DM4) | Relapsed/refractory B-cell lymphoma | CD19/DM4/SPDB | Severe blurred vision, microcystic corneal epithelial changesd | 17/39 | 2 (7 patients); 3 (5 patients); 4 (1 patient) | Reversibled | Younes et al.35 |
| SAR3419 (huB4-DM4) | Relapsed/refractory diffuse large B-cell lymphoma (CD19+ and CD20+) | CD19/DM4/SPDB | Blurred vision, dry eye, conjunctivitis, diplopia, eye irritation, corneal deposits, keratitis, keratoconjunctivitis, scotoma, optic neuropathy | Blurred vision (5 patients); dry eye (3 patients); diplopia (2 patients); all others (1 patient each) | 1–2 (except optic neuropathy associated with grade 3–4 blurred vision and eye irritation in a single patient) | Not specified | Coiffier et al.36 |
| SAR3419 (huB4-DM4) | Relapsed/refractory B-cell NHL | CD19/DM4/SPDB | Weekly: blurred vision, optic neuropathy, corneal deposit/microcysts.e | Weekly: 10/44 (blurred vision and corneal microcysts)e | 2 (corneal deposit) and 3 (optic neuropathy) | Reversible corneal toxicity (outcome of bilateral uveitis unknown due to patient death) | Ribrag et al.37 |
| Optimized schedule: blurred vision, bilateral uveitis w/decreased visual acuity; optic neuropathy (with blurred vision), diplopia, eye irritation | Optimized schedule: 4/25 | ||||||
| SGN-CD19A | Relapsed or refractory B-cell NHL, mantle cell lymphoma, or grade 3 follicular lymphoma | CD19/MMAF (auristatin)/mc | Blurred vision, dry eye, keratopathy, microcystic keratopathy | Blurred vision (59%), dry eye (39%), keratopathy (23%), microcystic keratopathy (57%) | Grade 3 or 4 in 4 patients receiving higher doses; otherwise, mostly grade 1–2 | Resolved or improved following treatment with steroid eye drops | Moskowitz et al.38 |
| SGN-CD19A | Relapsed or refractory B-lineage acute leukemia and highly aggressive lymphoma | CD19/MMAF (auristatin)/mc | Blurred vision, dry eye, superficial microcystic keratopathy | Superficial microcystic keratopathy in 13 adult patients (34%) and 1 pediatric patient (9%) | Grade 3/4 corneal AEs in 4 adult patients | Majority resolved or improved to grade 1–2 with steroid eye drops | Fathi et al.39 |
| AVE9633 | Relapsed/refractory acute myeloid leukemia | CD33/DM4/SPDB | Keratitis (dose-limiting) | 1/52 | 3 | Reversible | Lapusan et al.43 |
| SGN-75 | CD70+ metastatic RCC or relapsed/refractory NHL | CD70/MMAF (auristatin)/mc | Iridocyclitis | Not specified | 2 | Not specified | Thompson et al.48 |
| SGN-75 | CD70-positive relapsed/refractory NHL or metastatic RCC | CD70/MMAF (auristatin)/mc | Corneal epitheliopathy, dry eye, blurred vision, keratitis | Q3week dosing (57%): Corneal epitheliopathy (15%), dry eye (30%), blurred vision (11%), keratitis (9%) | Q3week dosing: ≥ Grade 3 in 23% | Generally reversible (resolved or resolving) with artificial tears and steroid eye drops | Tannir et al.47 |
| Weekly dosing (36%): | Weekly dosing: | ||||||
| Dry eye (27%), blurred vision (18%) | Grade 3: 1 patient with dry eye | ||||||
| SAR566658 | CA6+ advanced solid tumors | DS6/DM4/SPDB | Keratitis | 11/34 | 3 (2 patients); others not specified | Reversible | Boni et al.50 |
| Gemtuzumab ozogamicin | Acute myeloid leukemia | CD33/calicheamicin/hydrazone | Ocular bleeding (anatomic location not specified) | 1/9 | 4 | Not specified | Piccaluga et al.13 |
| MEDI-547 | Relapsed or refractory solid tumors | Ephrin type A receptor 2 (EphA2)/mcMMAF (auristatin)/mc | Eye pain, conjunctival hemorrhage | 1/6 (each for eye pain and hemorrhage) | Not specified (but classified as “serious”) | Not specified | Annunziata et al.58 |
| Lorvotuzumab mertansine (IMGN901) | CD56+ solid tumors | CD56/DM1/SPP | Eye redness | Total 3/64; 1/29 (4–48 mg/m2/day); 1/22 (75 mg/m2/day; 1/2 (94 mg/m2/day) | 1–2 | Not specified | Woll et al.63 |
| Lorvotuzumab mertansine (IMGN901) | Merkel cell carcinoma | CD56/DM1/SPP | Cortical blindness (consistent with reversible posterior leukoencephalopathy syndrome) | Single patient (case report) | Not specified | Slow progressive improvement with persistent visual field deficit | Wilson et al.64 |
| BT062 | Relapsed/refractory multiple myeloma | CD138/DM4/SPDB | Dry eyes, blurred vision, epithelial corneal damage, crystal inclusions | One patient with dry eyes/blurred vision; 1 patient with corneal epithelial disease/inclusions | 2 | Not specified | Chanan-Khan et al.67 |
| IMGN853 | FRα+ solid tumors | FRα/DM4/SPDB | TBW dosing: punctate keratitis, blurred vision, unspecified other ocular toxicity | TBW dosing: 4/11 at 5.0 mg/kg; 5/5 at 7.0 mg/kg | TBW dosing: 1–3 AIBW dosing: 1–2 for all AEs | Reversible | Moore et al.68 |
| AIBW dosing: punctate keratitis, blurred vision, retinopathy, floaters | AIBW dosing: 1/7 at 5.0 mg/kg; 3/7 at 6.0 mg/kg | ||||||
| IMGN853 | Platinum-resistant epithelial ovarian cancer | FRα/DM4/SPDB | Blurred vision, keratitis, punctate keratitis, corneal epithelial microcysts, retinal vein occlusion/vision impairment, corneal cyst, eye pain | Blurred vision (∼50%), keratitis or punctate keratitis (<20% each), corneal epithelial microcysts (1 patient), retinal vein occlusion/vision impairment (2 patients), corneal cyst (2 patients), eye pain (1 patient) | All ≤ grade 3 | Manageable with dose modifications | Moore et al.70 |
| AGS-16M8F-MMAF and AGS-16C3F-MMAF | Refractory RCCs (clear cell and papillary) | ENPP3/MMAF (auristatin)/mc | Most commonly reversible keratopathy, but otherwise not specified | AGS-16M8F: 8/26 | AGS-16M8F: 1 ≥ grade 3 | Reversible | Thompson et al.72 |
| AGS-16C3F: 29/34 | AGS-16C3F (any dose): 12 ≥ grade 3 | ||||||
| AGS-16C3F (1.8 mg/kg): 12/13 |
US Department of Health and Human Services. “Common terminology criteria for adverse events (CTCAE) version 4.0.” National Institutes of Health, National Cancer Institute (2009).
Incidence of conjunctivitis, photophobia, and swollen tear duct was reported as 1/24 for each, respectively. Whether these AEs were observed in separate patients was not specified.
One patient with a history of glaucoma developed grade 3 glaucoma and transient grade 4 reduced visual acuity, reported as unrelated to T-DM1. The patient remained on therapy without recurrence.
Most common finding was bilateral microcystic corneal epitheliopathy, typically starting at corneal periphery in a ring-like manner, migrating toward the papillary axis with occasional whitish clumping at the epithelial level. Corneal changes were reversible in all patients, and the single patient with grade 4 corneal changes experienced resolution to baseline within 3 days of discontinuation. When additional doses were administered following a previous ocular AE, corneal toxicity was recurrent with subsequent cycles, but again reversible in all patients.
Most common finding at slit-lamp examination was bilateral corneal epitheliopathy with microcystic appearance typically starting at the corneal periphery in a ring-like manner, migrating toward the axis with occasional whitish clumping at the epithelial level. Patients tear function and corneal thickness were largely not affected and the rest of the examination was unremarkable.
ADCs, antibody-drug conjugates; AIBW, adjusted ideal body weight; ENPP3, ectonucleotide pyrophosphatase/phosphodiesterase 3; FRα; folate receptor α; GO, gemtuzumab ozogamicin; HER2, human epidermal growth factor receptor 2; MMAF, monomethyl auristatin F; NHL, non-Hodgkin lymphoma; RCC, renal cell carcinoma; TBW, total body weight.