Abstract A141: Incidence of pulmonary and hematologic 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 trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate linked to a topoisomerase I inhibitor, recently approved for advanced HR-positive/HER2-negative breast cancer and non-small cell lung cancer. While Dato-DXd has shown strong efficacy in these settings, emerging data have raised concerns about pulmonary toxicities such as interstitial lung disease (ILD) and pneumonitis. Conversely, its hematologic toxicity profile may be more favorable than traditional chemotherapies. This meta-analysis synthesizes phase III trial data to quantify these risks in patients with advanced or metastatic cancer receiving Dato-DXd. Methods: A comprehensive literature search was performed using EMBASE and MEDLINE databases from inception through July 5, 2025. Phase III randomized controlled trials (RCTs) evaluating Dato-DXd in advanced or metastatic cancer and reporting pulmonary and hematologic adverse events (AEs) were included. The Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q-statistic. 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 in the analysis. The incidence of any-grade treatment-related ILD or pneumonitis was 5.8% in the Dato-DXd group versus 1.9% in the control group (RR 3.01; 95% CI: 1.61–5.61; p=0.0005). High-grade treatment-related ILD or pneumonitis occurred in 2.1% of patients receiving Dato-DXd compared to 0.6% in the control group (RR 3.15; 95% CI: 1.10–8.98; p=0.03). The rate of any-grade treatment-related pneumonitis was 3.8% with Dato-DXd versus 1.4% with control (RR 2.62; 95% CI: 1.26–5.45; p=0.01). Hematologic AEs were significantly lower in the Dato-DXd group. Any-grade anemia was reported in 12.8% of patients treated with Dato-DXd versus 20.1% with control (RR 0.64; 95% CI: 0.49–0.82; p=0.0004). The incidence of any-grade neutropenia was 8.1% in the Dato-DXd arm compared to 35.1% in the control arm (RR 0.23; 95% CI: 0.17–0.30; p<0.00001), and high-grade neutropenia occurred in 0.9% versus 27.5%, respectively (RR 0.03; 95% CI: 0.01–0.07; p<0.00001). Any-grade leukopenia was seen in 5.3% of Dato-DXd–treated patients compared to 16.4% in the control (RR 0.33; 95% CI: 0.23–0.47; p<0.00001), while high-grade leukopenia occurred in 0.3% versus 9.7% (RR 0.04; 95% CI: 0.01–0.14; p<0.00001). There was no statistically significant difference observed in the incidence of high-grade treatment-related pneumonitis, any-grade treatment-related ILD, high-grade treatment-related ILD, or high-grade anemia. Conclusion: Dato-DXd was associated with a higher risk of pulmonary AEs, including ILD and pneumonitis, but demonstrated significantly lower rates of hematologic AEs such as neutropenia, leukopenia, and anemia. These findings support close pulmonary monitoring and highlight a favorable hematologic safety profile in patients with advanced or metastatic cancer. Citation Format: Jason Ta, Rishi K. Nanda, Daniel T. Jones, Ramaditya Srinivasmurthy, Abbas Hussain, Riccesha Hattin, Clinton Lam, Kyaw Z. Thein. Incidence of pulmonary and hematologic 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 A141.