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Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate comprised of a topoisomerase I inhibitor payload and a monoclonal antibody directed to trophoblast cell-surface antigen 2, a protein that is broadly expressed in several types of solid tumors. In the TROPION-Lung01 phase III trial (NCT04656652), Dato-DXd demonstrated statistically significant improvement in median progression-free survival (mPFS) over docetaxel (4.4 vs. 3.7 months, hazard ratio [HR]=0.75, 95% confidence interval [CI], 0.62-0.91, P=.004]) in patients with previously treated metastatic non-small cell lung cancer (mNSCLC). Improvement in PFS was demonstrated in patients with nonsquamous mNSCLC (mPFS: 5.5 vs. 3.6 months, HR = 0.63, 95% CI, 0.51-0.79) and those with NSQ mNSCLC and actionable genomic alterations (mPFS: 5.7 vs 2.6 months, HR = 0.35, 95% CI, 0.21-0.60). A pooled analysis of previously treated patients with epidermal growth factor receptor mutation-positive NSCLC from TROPION-Lung01 and TROPION-Lung05 (NCT04484142) treated with Dato-DXd supported clinical activity (mPFS: 5.8 months, 95% CI, 5.4-8.2). In the TROPION-Breast01 phase III trial (NCT05104866), Dato-DXd demonstrated statistically significant improvement in mPFS over the investigator's choice of chemotherapy (6.9 vs. 4.9 months, HR = 0.63, 95% CI, 0.52-0.76, P<.0001) in patients with previously treated post-endocrine therapy hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. Dato-DXd also demonstrated a distinct safety profile in both trials. The successful implementation of any new anticancer therapy requires learning how to prevent, monitor, and manage treatment-related adverse events (AE). Information can be gained from real-world clinical practices, institutional approaches, and multidisciplinary teams who treat patients with Dato-DXd to provide a better patient experience and improved outcomes. Here, we discuss practical insights and management and treatment of key AEs from Dato-DXd, including oral mucositis/stomatitis, nausea and vomiting, ocular surface events, and interstitial lung disease garnered from a multidisciplinary team of health care professionals experienced in treating patients with Dato-DXd.