3MO HER2 expression and early response to patritumab deruxtecan (HER3-DXd) in early-stage hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC): A correlative analysis from SOLTI-TOT-HER3 trial

HER3-DXd and trastuzumab deruxtecan (T-DXd) are antibody-drug-conjugates (ADCs) directed against HER3 HER2, respectively. Both drugs have shown efficacy in patients (pt) with HR+/HER2- BC. Baseline protein or mRNA levels do not predict from HER3-DXd. Here, we aimed to evaluate the association of early response HER2 levels. TOT-HER3 (NCT04610528), a window-of-opportunity trial, evaluated single dose 77 pts untreated BC Part A (6.4 mg/kg) 17 B (5.6 mg/kg). Primary objective was CelTIL score [a surrogate that combines tumor cellularity tumor-infiltrating lymphocytes] variation between baseline day 21 samples. defined as an absolute increase 20 at 21. expression determined by immunohistochemistry (IHC). RNA DNA were purified FFPE samples analyzed using nCounter VHIO-300 NGS platforms, Logistic regression models area under ROC Curve (AUC) estimated performance IHC, copy-number (CN) response. In A, IHC status 32% 0, 38% 1+ 30% 2+. Distribution high responders 40% 45% 13% 2+ (p=0.034). High ERBB2 RNA-based amplicon signatures significantly associated low (ERBB2: Odds Ratio [OR]=0.34, p<0.001, AUC=0.71; amplicon: OR=0.20, p=0.005, AUC=0.74). The independent (p=0.002), PAM50 subtype (p=0.001) proliferation (p=0.003). CN signal found (p=0.005). will be independently validated B. Low early-stage might highly active HR+ very levels, thereby offering new therapeutic paradigm this subset patients.