Abstract Background: In the primary analysis of the phase 3 TROPION-Breast02 study (NCT05374512), 1L Dato-DXd showed statistically significant and clinically meaningful improvements in overall survival (HR: 0.79 95% CI 0.64, 0.98; p=0.0291) and progression-free survival (HR: 0.57 95% CI 0.47, 0.69; p0.0001) vs investigator’s choice of chemotherapy (ICC) in pts with locally recurrent inoperable or metastatic TNBC for whom immunotherapy was not an option. Despite more than double the median duration of treatment (tx), rates of grade (G)≥3 and serious treatment-related adverse events (TRAEs) were similar, and discontinuations were lower, with Dato-DXd vs ICC. Here we report additional safety analyses. Methods: The TROPION-Breast02 study design has been previously reported; safety was a secondary endpoint. Exposure-adjusted incidence rates (EAIRs) of AEs were derived from a post-hoc analysis, and expressed as subject rate (per 100 pt years), calculated as number of pts with AEs divided by the total duration of treatment across all pts, x100. Tx-related AEs of special interest (AESIs) for Dato-DXd included oral mucositis/stomatitis, ocular surface events (OSEs), and interstitial lung disease (ILD)/pneumonitis. For prevention/management of AESIs in the Dato-DXd arm, steroid-based mouthwash 4x daily was highly recommended but not mandated, and pts were advised to use artificial tears and avoid contact lenses. Ophthalmological assessments were required at baseline, as clinically indicated and at end of tx; additional assessments were required every 3 cycles while on tx in the Dato-DXd arm only. Results: At data cut-off (DCO: 25 Aug 2025), 319 pts had received Dato-DXd and 309 had received ICC; median total tx duration was 8.5 months vs 4.1 months in the Dato-DXd vs ICC arm. Absolute incidence rates of TRAEs with Dato-DXd vs ICC were: all-grade, 92.8% vs 83.2%; G≥3, 32.9% vs 28.8%; serious, 9.1% vs 8.4%; leading to tx discontinuation, 4.4% vs 7.4%. EAIRs of TRAEs per 100 pt years were lower with Dato-DXd vs ICC: all-grade, 104.0 vs 175.9; G≥3, 36.9 vs 60.9; serious, 10.2 vs 17.8; leading to tx discontinuation, 4.9 vs 15.7. Tx-related oral mucositis/stomatitis was reported in 192 pts (60%) in the Dato-DXd arm; most events were G1 (78 pts 24%) or G2 (87 pts 27%), and no events led to tx discontinuation. Median time to onset (TTO) was 26 days (range 1-603). Among 114 pts with G≥2 oral mucositis/stomatitis, events had resolved to G≤1 in 103 pts (90%) at DCO; median time to resolution (TTR) was 40.5 days (range 4-510). OSEs were reported in 149 pts (47%) in the Dato-DXd arm, were mostly G1 (76 pts 24%) or G2 (50 pts 16%), and led to tx discontinuation in 3 pts (0.9%). Median TTO was 77.5 days (range 2-912). Among 73 pts with G≥2 OSEs, events had resolved to G≤1 in 49 pts (67%) at DCO; median TTR was 64 days (range 8-528). Adjudicated drug-related ILD/pneumonitis was reported in 9 pts (3%) in the Dato-DXd arm: G1 in 1 pt, G2 in 7 pts, and G5 in 1 pt (characterized by investigator as G3 pneumonitis, with death assessed as related to breast cancer). Adjudicated drug-related ILD/pneumonitis led to tx discontinuation in 3 pts (0.9%). Median TTO was 259 days (range 161-588); 4/9 events had resolved at DCO, and median TTR was 112.5 days (range 13-159). Conclusion: In TROPION-Breast02, pts were on tx for longer in the Dato-DXd vs ICC arm; exposure-adjusted rates of TRAEs were lower with Dato-DXd vs ICC. Tx-related AESIs with Dato-DXd were mainly G1/2, rarely led to treatment discontinuation, and were mostly resolved to G≤1 at DCO. These data further support Dato-DXd as the new 1L standard of care for pts with locally recurrent inoperable or metastatic TNBC for whom immunotherapy is not an option. Citation Format: T. A. Traina. First-line (1L) datopotamab deruxtecan (Dato-DXd) vs chemotherapy in patients (pts) with locally recurrent inoperable or metastatic triple negative breast cancer (TNBC) for whom immunotherapy was not an option: Additional safety analyses from the TROPION-Breast02 study abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-03-05.
T. A. Traina (Tue,) studied this question.