Introduction. Antibody-drug conjugates (ADCs) represent a new class of molecular-targeted drugs, which are being developed to selectively target tumor cells and minimize toxicities. Three ADCs, namely trastuzumab emtansine (TDM-1), sacituzumab govitecan, and trastuzumab deruxtecan, are currently approved for the treatment of metastatic breast cancer (MBC). Acute gastrointestinal toxicities are relatively frequent with these agents. We performed a pooled analysis evaluating gastrointestinal adverse events (AEs) in patients with MBC treated with ADCs. Methods. PubMed, Embase, and the Cochrane Library were searched from inception until December 2020 for phase 2 and 3 trials reporting frequency and severity of gastrointestinal AEs in patients treated with ADCs. Data were collected for nausea, vomiting, diarrhea, constipation, and abdominal pain: overall and grade 3-4 toxicity rates according to NCI-CTCAE were described and expressed as proportions. A pre-specified subgroup analysis according to type of agent was also performed. Results. Ten studies, involving a total of 4020 patients, were included in the analysis. Gastrointestinal AEs were very frequent with sacituzumab govitecan and trastuzumab deruxtecan but were mostly low-grade. These novel ADCs were characterized by a significantly higher incidence of nausea (65.6% with sacituzumab govitecan, 77.2% with trastuzumab deruxtecan), vomiting (43.7% and 46.6%), and diarrhea (59.7% and 30.2%) compared to TDM-1. Diarrhea was the main AEs associated with sacituzumab govitecan (grade 3 in 7.5% of patients). Abdominal pain and constipation were reported less frequently. Conclusions. Gastrointestinal AEs, especially nausea and diarrhea, are common in patients with MBC treated with novel ADCs. Prevention and treatment of these side effects are essential to maintain the dose intensity of ADCs and optimize the treatment compliance of patients. Table. Gastrointestinal toxicities of the different ADCs in MBC patients in the current pooled analysis.Gastrointestinal toxicities Toxicity pooled % (CI 95%)Sacituzumab govitecanTDM-1Trastuzumab deruxtecanp*p**p#NauseaAll gradesG3-G457.8 (46.9-68)2.2 (1-4.9)65.6 (61-70)4.3 (2.2-8.3)38.1 (32-44.5)0.8 (0.5-1.2)77.2 (72-81.6)2.6 (0.2-30.6)< 0.01< 0.01< 0.01< 0.01< 0.010.71DiarrheaAll grades G3-G434 (21.8-48.8)2.4 (1.7-3.3)59.7 (52.4-66.6)7.5 (4.3-12.7)17.5 (11.-25.4)0.9 (0.6-1.6)30.2 (25.3-35.7)2.4 (1.1-4.9)< 0.01< 0.01< 0.010.03< 0.010.015VomitingAll grades G3-G432.5 (23.6-42.8)2.7 (1.4-5)43.7 (33.5-54.5)4.4 (1.7-10.8)18.2 (15.3-21.4)1.3 (0.9-1.8)46.6 (41-52.3)4.4 (2.5-7.4)< 0.01< 0.01< 0.01< 0.01NSNSAbdominal painAll grades G3-G414.8 (9.4-22.5)1.2 (0.7-2.1)20.1 (11.9-31.8)1.3 (0.4-3.9)6.2 (4.2-9)1.2 (0.5-2.9)14.5 (9.8-21)0.9 (0.3-3.1)< 0.01NS< 0.01NSNSNSConstipationAll grades G3-G428.7 (20.4-38.9)0.6 (0.4-0.9)32.2 (18.6-49.6)0.8 (0.3-2.6)18 (12-26.1)0.5 (0.3-0.9)35.9 (30.7-41.5)0.7 (0.2-2.7)< 0.01NS< 0.01°NSNSNS* Statistically significant difference (p < 0.05) among the three ADCs.** Statistically significant difference (p < 0.05) for TDM-1 versus the other two ADCs.# Statistically significant difference (p < 0.05) for sacituzumab govitecan versus trastuzumab deruxtecan.° This value was not significant for T-DM1 versus sacituzumab govitecan comparison.CI, confidence interval; NS, not significant. Citation Format: Pierluigi di Mauro, Rebecca Pedersini, Fausto Petrelli, Antonio Ghidini, Vito Amoroso, Lara Laini, Maria Chiara Parati, Paolo Bossi, Alfredo Berruti. Gastrointestinal toxicity of antibody-drug conjugates (ADCs) in metastatic breast cancer: A pooled analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-15.