Phase II Exploratory Study of Neoadjuvant Disitamab Vedotin and Penpulimab in HER2-low Stage II-III Breast Cancer (NeoPanDa04)

HER2-low breast cancer lacks effective targeted options in the curative setting. We evaluated the efficacy, safety, and exploratory biomarker correlates of neoadjuvant disitamab vedotin (HER2-targeted antibody–drug conjugate) plus penpulimab (PD-1 inhibitor) in stage Ⅱ–Ⅲ disease (NCT05726175). In a prospective single-arm study, patients with newly diagnosed stage II–III HER2-low breast cancer (IHC 1 + or 2+/FISH−) received disitamab vedotin plus penpulimab every 3 weeks for six cycles before surgery. The primary end point was pathologic complete response (pCR). Secondary end points included objective response rate (ORR) and safety. Exploratory analyses incorporated multi-omic profiling (proteomics, multiplex immunofluorescence, RNA sequencing) and integrative modeling to derive predictive biomarkers. In the per-protocol set, pCR was 25.0% (4/16) and ORR 56.3% (9/16). At surgery, 31.3% achieved residual cancer burden (RCB) 0–1. Numerically higher pCR rates were seen in PD-L1–positive versus –negative tumors (33.3% v 14.3%) and in HER2 IHC 2+/FISH − versus IHC 1 + tumors (37.5% v 12.5%). Treatment was generally well tolerated: grade ≥ 3 events occurred in 25%, with no treatment-related deaths. Exploratory multi-omics yielded a baseline response prediction model (BRPscore; CCL19 + M2/M1 macrophage ratio) that correctly discriminated all pCR cases with strong discriminatory capacity (AUC 0.89), and identified MCP-1 as the most consistent biomarker across timepoints. In conclusion, neoadjuvant disitamab vedotin plus penpulimab produced a 25% pCR with manageable safety in stage II–III HER2-low breast cancer. The integration of a BRPscore with MCP-1 as a dynamic biomarker provides proof-of-concept for biomarker-driven patient selection and adaptive monitoring, supporting further randomized evaluation of ADC–ICI combinations.