Neoadjuvant antibody-drug conjugates for early-stage breast cancer: A systematic review and meta-analysis

Pathologic complete response (pCR) is a key endpoint of neoadjuvant therapy in early-stage breast cancer (EBC), associated with improved survival, particularly in triple-negative and human epidermal growth factor receptor 2 (HER2)-positive disease. More recently, antibody-drug conjugates (ADCs), established in metastatic disease, are being evaluated in the neoadjuvant setting.

We systematically searched for studies of EBC patients treated with neoadjuvant ADCs, alone or in combination. Meta-analyses were carried out using a random-effects model, with heterogeneity assessed via I² statistics and Cochran's Q test.

Twenty-four studies were included, 22 (2,363 patients) contributed to the pCR analysis, predominantly phase I/II trials and two phase III studies. Nine ADCs targeting HER2, trophoblast cell surface antigen 2 (TROP2), LIV1 or human epidermal growth factor receptor 3 (HER3), and incorporating six distinct payload classes were identified. The pooled pCR rate was 38.34% (95% CI 29.36-47.72; I² = 92.8%), highest among hormone receptor (HR)-negative/HER2+ tumors (65.06%), followed by HR+/HER2+ (47.53%), TNBC (29.37%), and HR+/HER2- (2.94%) (p<0.0001). By target, pCR rates were 43.93% for HER2-directed ADCs, 41.41% for TROP2, 16.57% for LIV1, and 3% for HER3. Common all-grade adverse events (AEs) included nausea (64.52%), diarrhea (48.24%), alopecia (39.19%), alanine aminotransferase elevation (38.80%), aspartate aminotransferase elevation (34.87%), neutropenia (29.53%), vomiting (25.95%), and anemia (24.89%). Grade ≥3 AEs occurred in 25.06% of patients.

Neoadjuvant ADC-based strategies yield clinically meaningful pCR rates in EBC, with the greatest benefit in HER2+ disease, supporting further investigation and biomarker-guided patient selection.