Abstract C055: Incidence of gastrointestinal adverse events in advanced or metastatic cancer patients treated with Datopotamab Deruxtecan: A meta-analysis of phase III randomized controlled trials

Abstract Background: Datopotamab deruxtecan (Dato-DXd) is a TROP2-directed antibody-drug conjugate linked to a topoisomerase I inhibitor. It received FDA approval in January 2025 for HR-positive, HER2-negative metastatic breast cancer and accelerated approval in June 2025 for EGFR-mutated advanced NSCLC. While Dato-DXd has demonstrated strong clinical activity, gastrointestinal (GI) toxicities such as nausea, diarrhea, and stomatitis have been frequently reported. These adverse events may affect treatment adherence and patient quality of life. This meta-analysis evaluated the incidence and severity of GI adverse events associated with Dato-DXd in phase III randomized controlled trials. Methods: A comprehensive literature search was conducted using MEDLINE and EMBASE through July 5, 2025. Eligible studies included phase III randomized controlled trials (RCTs) evaluating Dato-DXd in advanced or metastatic cancers that reported GI AEs. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using the Mantel-Haenszel method. Heterogeneity was assessed via Cochran’s Q statistic, and a fixed-effects model was applied. Results: A total of 1,298 patients from two phase III RCTs (TROPION-Breast01, n=711; TROPION-Lung01, n=587) were included. The incidence of GI AEs was significantly higher in the Dato-DXd arm compared to control. Any grade mucositis/stomatitis occurred in 54.2% versus 15.8% (RR 3.44; 95% CI: 2.84–4.17; p<0.00001), and high-grade mucositis/stomatitis in 6.8% vs 2.0% (RR 3.38; 95% CI: 1.84–6.20; p<0.0001). Similarly, any grade stomatitis was seen in 49.9% vs 14.5% (RR 3.44; 95% CI: 2.81–4.22; p<0.00001), and high-grade stomatitis in 6.5% vs 1.9% (RR 3.50; 95% CI: 1.86–6.57; p=0.0001). Other mucosal-related toxicities included oropharyngeal pain (4.4% vs 0.9%; RR 4.04; 95% CI: 1.78–9.16; p=0.0008), mouth ulceration (2.7% vs 0.9%; RR 2.93; 95% CI: 1.17–7.32; p=0.02), and oral pain (1.7% vs 0.5%; RR 3.58; 95% CI: 1.00–12.76; p=0.05). Nausea of any grade occurred in 43.4% of patients receiving Dato-DXd compared to 20.4% in the control group (RR 2.12; 95% CI: 1.78–2.53; p<0.00001), while any grade decreased appetite was reported in 18.0% vs 13.6% (RR 1.32; 95% CI: 1.03–1.71; p=0.03). Interestingly, diarrhea was less frequent with Dato-DXd. Any grade diarrhea occurred in 8.7% vs 15.3% (RR 0.57; 95% CI: 0.42–0.77; p=0.0003), and high-grade diarrhea in 0.2% vs 1.2% (RR 0.17; 95% CI: 0.03–0.97; p=0.05). No statistically significant differences were observed in high-grade mouth ulceration, high-grade nausea, or high-grade decreased appetite. Conclusion: This meta-analysis demonstrates a significantly increased risk of GI adverse events in patients receiving Dato-DXd compared to standard therapies, particularly for mucositis/stomatitis and nausea. Notably, Dato-DXd was associated with a lower incidence of diarrhea. These findings underscore the importance of vigilant monitoring and proactive supportive care to mitigate GI toxicities and maintain treatment adherence. Citation Format: Ramaditya Srinivasmurthy, Jason Ta, Daniel T. Jones, Abbas Hussain, Riccesha Hattin, Rishi K. Nanda, Kyaw Z. Thein. Incidence of gastrointestinal adverse events in advanced or metastatic cancer patients treated with Datopotamab Deruxtecan: A meta-analysis of phase III randomized controlled 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 C055.