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.