Abstract Background: Despite advances in anti-HER2 therapy, treatment options remain limited for patients (pts) with HER2-positive (HER2+) advanced breast cancer (ABC) who have progressed on at least trastuzumab and taxane in China. DP303c is a novel antibody-drug conjugate targeting HER2, composed of a humanized anti-HER2 monoclonal antibody conjugated to monomethyl auristatin E. This phase III study compared the efficacy and safety of DP303c with T-DM1 in pts with HER2+ ABC who had received prior trastuzumab and taxane therapy. Methods: Adult pts with HER2+ ABC previously treated with trastuzumab and taxane were randomly assigned (1:1) to receive DP303c (3.0 mg/kg Q3W) or T-DM1 (3.6 mg/kg Q3W). Pts were stratified by number of lines of previous systemic therapy (≤1 vs. 1), prior pertuzumab treatment (Yes vs. No), and visceral metastasis(Yes vs. No). The primary endpoint was PFS assessed by a blinded independent review committee (BIRC). Secondary endpoints included investigator-assessed PFS, overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and safety. Results: Between Mar 28, 2024 and April 25, 2025, 448 pts were randomized (DP303c, n=226; T-DM1, n=222). Baseline characteristics were well balanced. Median age was 54 (range:25, 78) years; median weight 60.0 (range:36, 99.5) kg; 78.8% were HER2 IHC 3+, 52.0% were hormone receptor-positive, 68.8% had visceral metastasis and 11.4% had intracranial metastases in intent-to-treat population. Overall, 59.8% had received ≥2 lines of advanced systemic therapy, with 51.1% previously treated with pertuzumab and 55.8% with HER2 tyrosine kinase inhibitors . At interim analysis (cut-off date: July 8, 2025; median follow-up: 7.4 months), BIRC-assessed PFS was significantly improved with DP303c (median PFS 8.8 months; 95% CI: 7.20, 9.92) vs T-DM1 (median PFS 5.8 months; 95% CI: 4.67, 7.10) (p0.0001), with a stratified hazard ratio (HR) of 0.56 (95% CI: 0.42, 0.75). Investigator-assessed PFS showed consistent results (median PFS 9.7 vs 6.9 months; p0.0001; HR 0.55, 95% CI: 0.41, 0.73). The confirmed ORR per BIRC was significantly higher with DP303c (62.8%; 95% CI: 56.17, 69.15) vs T-DM1 (42.8%; 95% CI: 36.19, 49.59), with a rate difference of 20.0% (95% CI: 10.93, 29.16). CBR per BIRC was 68.6% (95% CI: 62.10, 74.58) vs 50.9% (95% CI: 44.13, 57.65). OS was immature at this analysis. Treatment-emergent adverse events (TEAEs) occurred in 99.6% of DP303c and 99.1% of T-DM1 pts. The most common TEAEs (≥20%) with DP303c included corneal disorder, vision blurred, dry eye, peripheral sensory neuropathy, hyperlipidemia, alopecia, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, and weight decreased. Only 1 pt had ulcerative keratitis, with no corneal perforation or blindness in DP303c group. The most common TEAEs (≥20%) with T-DM1 were AST increased, platelet count decreased, ALT increased, corneal disorder, dry eye, vision blurred, neutrophil count decreased, white blood cell count decreased, hyperlipidemia, anemia, Gamma-glutamyltransferase increased, and hypercholesterolaemia. Permanent discontinuation due to treatment-emergent adverse events was observed in 2 pts (0.9%) receiving DP303c and 3 (1.4%) receiving T-DM1. One on-treatment death occurred in each group, judged to be unrelated to study treatment per investigator. Conclusion: DP303c demonstrated statistically significant and clinically meaningful improvement in PFS compared with T-DM1 in pts with HER2+ ABC who had been previously treated with trastuzumab and taxane. The safety profile of DP303c was manageable. These results support DP303c as a potential new treatment option for HER2+ ABC. Citation Format: X. Hu, J. Yu, T. Sun, Q. Zhang, H. Li, J. Yao, Y. Shi, T. Wu, X. Jia, Y. Shi, S. Ding, W. Chen, Y. Zeng, X. Zeng, Y. Yin, J. Wu, J. Sun, D. Luo, J. Nie, F. Li, Y. Liu, Z. Zhang, C. Yuan, C. Yang, H. Yang, C. Li, X. Ling, X. Wu, G. Li, Z. Li, Z. Pan, J. Zhang, Q. Zhou. Efficacy and safety of DP303c versus T-DM1 in HER2-positive advanced breast cancer: Interim analysis of a randomized, open-label, phase 3 trial 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 RF6-03.
Hu et al. (Tue,) studied this question.