Integrative Multiomics Profiling Reveals Immune Determinants of Response to Disitamab Vedotin Plus Penpulimab in HER2‐Low Breast Cancer

ABSTRACT This prospective single‐arm study evaluated neoadjuvant disitamab vedotin plus penpulimab in Stage II–III HER2‐low breast cancer (immunohistochemistry 1+ or 2+, fluorescence in situ hybridization‐negative), a population lacking targeted neoadjuvant options. Twenty patients received the combination every 3 weeks for six cycles before surgery. In the intention‐to‐treat population, the pathologic complete response (pCR) was 20.0% (four out of 20; 95% CI, 5.7–43.7%), and the objective response rate (ORR) was 45.0% (nine out of 20; 95% CI, 23.1–68.5%). Among 16 patients who completed protocol‐defined treatment and surgery, pCR was 25.0% (four out of 16; 95% CI, 7.3–52.4%), ORR was 56.3% (nine out of 16; 95% CI, 29.9–80.2%), and 31.3% achieved residual cancer burden Class 0–1. Grade ≥3 adverse events occurred in 25.0%; no treatment‐related deaths occurred. pCR‐associated tumors had a pretreatment immune‐active microenvironment enriched in inflammatory proteins, transcripts, and tumor‐infiltrating lymphocytes, whereas nonresponders displayed a higher M2/M1 macrophage ratio. An exploratory baseline score combining CCL19 and the M2/M1 ratio showed pCR/non‐pCR separation (AUC = 0.8889) but attenuated on internal validation (LOOCV AUC = 0.6667, optimism‐corrected bootstrap AUC = 0.8375). This combination showed preliminary antitumor activity with manageable safety; however, given the small sample size and wide confidence intervals, these findings preclude definitive conclusions about efficacy and warrant validation in larger randomized controlled trials.