Background: Tusamitamab ravtansine (tusa rav) is a novel antibody-drug conjugate (ADC) targeted to carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and delivering DM4, a cytotoxic maytansinoid. CEACAM5 is highly expressed in several tumor types, including nonsquamous non-small cell lung cancer (NSQ NSCLC). An open-label, Phase 1/2, dose-escalation/expansion study (NCT02187848) in patients with advanced solid tumors found the maximum tolerated dose of tusa rav to be 100 mg/m² every 2 weeks (Q2W) with a dose-limiting toxicity of microcystic keratopathy. Tusa rav had a favorable safety profile and, in patients with NSQ NSCLC with high CEACAM5 expression, promising antitumor activity. Methods: Here we evaluate pooled corneal safety results in patients (n = 186) who received tusa rav 100 mg/m² Q2W, including cohorts of patients with NSQ NSCLC, colorectal, gastric, or small cell lung cancers. Patients who had history of corneal disorders, contraindications to ocular prophylactic drops, or were unable to stop contact lens use for the study were ineligible. Artificial tear use was encouraged during the study. Results: In patients treated with tusa rav 100 mg/m² (median treatment duration 8.7 weeks [range 2–154]), corneal treatment-emergent adverse events (TEAEs) were reported in 56/186 (30.1%), with the worst grade being Grade 1 as asymptomatic (n = 7), Grade 2 (n = 33), and Grade 3 (n = 16). No patients had Grade 4 (perforation or blindness) or serious corneal adverse events. The most frequent corneal TEAEs were keratitis and keratopathy in 22% and 11.8% (Grade 3 in 6.5% and 2.7%) of 186 patients, respectively. Occurrence of Grade ≥2 corneal events was significantly associated with tusa rav exposure in Q2W dosing (including dose-escalation ≤150 mg/m²). Most patients with corneal TEAEs had first occurrence within the first 4 cycles (45/56), including 16 in Cycle 2 and none in Cycle 1. At analysis cut-off, corneal TEAEs had resolved in 40/56 (71.4%) patients. The median recovery time was 20.5 days (range, 8–264). Of the 186 patients, corneal TEAEs led to cycle delay in 15.6%, cycle delay with dose reduction in 7.0%, and no treatment discontinuations. Corneal TEAEs recurred in 19/56 (33.9%) patients with a median time to recurrence of 16 days. Primary prophylaxis (ophthalmic vasoconstrictor, corticosteroid gel, and/or cold masks at infusion) in only the right eye in 107 patients did not show benefit (98% of the 55 events were bilateral), supporting use of secondary prophylaxis only as needed in subsequent patients. Conclusions: Corneal TEAEs observed in the study were nonserious and typically reversible; management with dose modification allowed continuation of treatment. These results support the ongoing clinical development of tusa rav. Further investigation of the mechanisms of corneal TEAEs with ADCs and their management is necessary. Clinical trial information: NCT02187848.