Efficacy and safety of antibody-drug conjugates in gastrointestinal malignancies: A systematic review and meta-analysis of phase I-III trials.

Abstract

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.