e15035 Background: Antibody-drug conjugates (ADCs) represent a promising targeted therapy class for GI malignancies, with emerging activity across HER2, Trop-2, CLDN18.2, and other targets increasingly supporting tumor agnostic approaches. We conducted the first comprehensive systematic review and meta-analysis to synthesize efficacy and safety outcomes of ADCs across all GI malignancies from phase I-III trials. Methods: We conducted a systematic review and meta-analysis of phase I-III trials evaluating ADCs in GI malignancies, searching PubMed, EMBASE, ClinicalTrials.gov, Web of Science, Cochrane Library, and ASCO/ESMO/AACR proceedings through December 2025. Study-level data were pooled using random-effects models (R metafor package) with logit transformation for proportions (objective response rate ORR, disease control rate DCR, adverse events AEs) and log-scale pooling for medians (PFS, OS, DOR) with variance from 95% CIs, exponentiated to months. Restricted maximum likelihood estimation was employed. Results: Thirty-eight trials (N = 2,893 patients) were included, evaluating HER2-targeted, Trop-2, CLDN18.2, and other ADCs in advanced/pretreated GI cancers. The pooled ORR was 28.0% (95% CI: 23.0-33.7; I² = 87.4%), with a DCR of 74.2% (67.0-80.3; I² = 91%). Median PFS was 4.3 months (95% CI: 3.7-5.0; I² = 88.6%), median OS 9.6 months (8.2-11.3; I² = 84.1%), and median DOR 6.3 months (5.7-6.9; I² = 21.4%). Subgroup analyses showed ORR of 35.4% (29.8-41.5) with HER2-targeted ADCs, 33.4% (19.9-50.2) with CLDN18.2, 4.4% (1.4-12.7) with Trop-2; ORR was 32.7% (25.5-40.9) with topoisomerase I inhibitor payloads and 30.2% (15.2-51.1) with microtubule inhibitors such as MMAE. ORR was 35% in biliary tract cancers and 31.2% in gastric, with 21.4% in colorectal cancers and 21.7% in pancreatic cancers. ORR remained consistent across subsequent lines of therapy, with 27.0% (23.1-31.4; I² = 69.3%) in ≥2nd line and 26.4% (15.61-41.0; I² = 92.8%) in ≥3rd line settings. Grade ≥3 AE rate was 59.6% (54.5-64.5; I² = 79.4%) overall, with key toxicities including anemia (17.2%; 13.0-22.4), neutropenia (14.3%; 7.2-26.6), and ILD/pneumonitis (ILD; any grade 11.9%, ≥3 3.5%). ILD was higher with HER2 ADCs (any 13.1%, ≥3 3.6%), and neutropenia was predominant in pancreatic cohorts (32.8%). Grade ≥3 AEs occurred in 63.5-68.1% with topoisomerase payloads and 55.3% with microtubule payloads. Conclusions: This comprehensive meta-analysis demonstrates meaningful antitumor activity of ADCs in GI malignancies, supporting broad therapeutic potential, including and extending beyond HER2+ gastric cancer, particularly with novel targets like CLDN18.2 and in biliary/gastric subtypes. Safety profiles appear consistent with known ADC toxicities, though topoisomerase payloads and HER2 targeting confer higher risks of cytopenias and ILD, respectively.
Bawek et al. (Thu,) studied this question.