Abstract A095: Tolerability and ocular adverse events of Datopotamab Deruxtecan in advanced cancers: A meta-analysis of phase III trials

Abstract Background: Datopotamab deruxtecan (Dato-DXd) is a novel antibody-drug conjugate composed of a TROP2-targeting monoclonal antibody linked to a topoisomerase I inhibitor. It received FDA approval in January 2025 for unresectable or metastatic HR-positive, HER2-negative breast cancer based on the TROPION-Breast01 trial and was granted accelerated approval in June 2025 for EGFR-mutated, metastatic NSCLC following TROPION-Lung01. As Dato-DXd gains broader clinical use, attention has turned to its safety profile. While gastrointestinal and hematologic toxicities are documented, emerging data suggest increased ocular adverse events (OAEs), including dry eye, conjunctivitis, and keratitis, which may impact quality of life and treatment adherence. This meta-analysis evaluated the tolerability of Dato-DXd, focusing on the incidence and severity of OAEs in patients treated across phase III trials. Methods: For this meta-analysis, a comprehensive search of MEDLINE and EMBASE was conducted from inception through July 5, 2025, for phase III randomized controlled trials (RCTs) evaluating Dato-DXd in advanced or metastatic cancers. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using the Mantel-Haenszel method. A fixed effects model was applied, and heterogeneity was assessed using Cochran’s Q-statistic. Results: A total of 1,298 patients across two phase III RCTs (TROPION-Breast01: n=711; TROPION-Lung01: n=587) were included. Ocular toxicities were more common in the Dato-DXd group. Any-grade ocular surface events occurred in 31.7% of patients receiving Dato-DXd compared to 10.6% in the control arm (RR 2.98; 95% CI: 2.32–3.83; p<0.00001), and high-grade ocular surface events in 1.5% vs 0.0% (RR 10.74; 95% CI: 1.39–82.89; p=0.02). Specific events included any grade dry eye (15.1% vs 4.7%; RR 3.22; 95% CI: 2.18–4.75; p<0.00001), any grade keratitis (9.7% vs 2.8%; RR 3.47; 95% CI: 2.09–5.75; p<0.00001), any grade conjunctivitis (3.8% vs 0.6%; RR 6.10; 95% CI: 2.14–17.41; p=0.0007), and any grade increased lacrimation (7.0% vs 3.0%; RR 2.36; 95% CI: 1.40–3.98; p=0.001). High-grade dry eye and keratitis were not statistically significant.Dato[VD5.1]-DXd showed improved tolerability with fewer grade ≥3 TRAEs (23.0% vs 43.5%; RR 0.53; 95% CI: 0.45–0.62; p<0.00001), dose reductions (20.5% vs 30.0%; RR 0.69; 95% CI: 0.57–0.83; p=0.0001), and treatment interruptions (14.3% vs 18.9%; RR 0.76; 95% CI: 0.59–0.97; p=0.03). No significant differences were observed in serious TRAEs, TRAE-related deaths, or discontinuation due to TRAEs, mucositis/stomatitis, or ocular events. Conclusion: This meta-analysis shows that Dato-DXd increases the risk of any-grade ocular adverse events, including dry eye, keratitis, conjunctivitis, and increased lacrimation. Despite this, Dato-DXd showed better overall tolerability than control treatments, with fewer grade ≥3 adverse events, dose reductions, and treatment interruptions. Routine ophthalmologic monitoring is advised, and further research is needed to guide management. Citation Format: Daniel Thomas. Jones, Ramaditya Srinivasmurthy, Jason Ta, Rishi Kumar. Nanda, Abbas Hussain, Riccesha Hattin, Kyaw Zin. Thein. Tolerability and ocular adverse events of Datopotamab Deruxtecan in advanced cancers: A meta-analysis of phase III trials [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A095.