Abstract PS4-08-29: Neoadjuvant antibody-drug conjugates for early-stage breast cancer: a systematic review and meta-analysis

Abstract Background: Pathologic complete response (pCR) is a key endpoint of neoadjuvant systemic therapy in early-stage breast cancer (EBC) and is associated with improved survival in triple-negative (TNBC) and HER2-positive subtypes. Several antibody-drug conjugates (ADCs) have shown efficacy in the metastatic setting and are now under investigation for use in localized disease. Preliminary clinical evidence points to promising pCR rates with ADCs in EBC, even among biologically aggressive subtypes. This study evaluates the efficacy and safety of neoadjuvant ADCs in EBC. Methods: We systematically searched PubMed, Embase, and Cochrane databases for studies including patients diagnosed with EBC who received neoadjuvant ADCs. All EBC subtypes were included, and ADCs could be administered as monotherapy or in combination with other systemic agents. Studies were excluded if they involved adjuvant therapy, metastatic disease, or lacked disaggregated data for the ADC arm. Meta-analyses were performed using a random-effects model, with heterogeneity assessed via the I2 statistic and Cochran’s Q test. Sensitivity analyses were conducted using meta-analyses of proportions with subgroup analyses. Results: Among 2,809 screened studies, 23 met the inclusion criteria. A total of 1,762 patients treated with ADCs were included in the pCR analysis. Most of the included studies were phase I/II trials, evaluating nine distinct ADCs, directed against four molecular targets (HER2, TROP2, HER3, and LIV1) and utilizing six different payload types. The pooled pCR rate across all neoadjuvant ADC regimens was 36.94% (95% CI 27.44-47.58). A statistically significant difference (p<0.0001) was observed in the subgroup analysis by histological subtype, with the highest pCR rates seen in HER2-positive disease (52.51%; 95% CI 45.50-59.43), followed by TNBC (29.5%; 95% CI 22.4-37.7), and HR+/HER2- (4.05%; 95% CI 2.00-7.75). Meta-analysis of proportions revealed a pCR rate of 43.5% (95% CI 33.48-54.99) for HER2-targeted ADCs, and 41.4% (95% CI 28.7-55.4) for TROP2-targeted ADCs. In an analysis stratified by payload mechanism of action, topoisomerase I inhibitor-based ADCs demonstrated a pooled pCR rate of 29.91% (95% CI 14.16-52.47), while anti-microtubule-based ADCs showed pCR of 42.09% (95% CI 33.87-50.77) (p=0.3028). The most frequent treatment-related adverse events (any grade) included nausea (61.03%), diarrhea (49.40%), alopecia (40.68%), ALT elevation (39.39%), AST elevation (35.45%), neutropenia (30.24%), anemia (28.40%), vomiting (26.32%), and thrombocytopenia (17.46%). Grade ≥3 adverse events were less common, with neutropenia being the most frequent (18.25%), followed by ALT elevation (5.46%), thrombocytopenia (4.99%), and diarrhea (3.67%). Conclusion: Neoadjuvant ADCs demonstrate promising pCR rates in early-stage breast cancer, particularly in HER2-positive subtype. Treatment-related adverse events were frequent, but generally manageable. These findings support further investigation of ADCs in neoadjuvant treatment strategies. Citation Format: G. B. Silva, A. R. Simões, R. H. da Silva, R. L. Nohmi, G. O. Bretas, M. O. Andrade. Neoadjuvant antibody-drug conjugates for early-stage breast cancer: a systematic review and meta-analysis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-08-29.