Navigating Antibody-Drug Conjugate Sequencing in Gastric Cancer: Cross-Resistance Biology, Target Switching, and...

Antibody-drug conjugates (ADCs) have reshaped the therapeutic landscape of advanced gastric cancer, with trastuzumab deruxtecan (T-DXd) and disitamab vedotin (RC48) establishing new standards for HER2-positive disease, and a wave of Claudin 18.2 (CLDN18.2)-directed ADCs demonstrating promising early efficacy. However, as the arsenal of effective ADCs expands, clinicians increasingly confront a question that existing guidelines leave unanswered: how should ADCs be sequenced after disease progression?

This review synthesizes the emerging biology of ADC cross-resistance in gastric cancer, with particular attention to payload-specific resistance mediated by ABC transporters, the impact of linker technology on bystander killing, and the implications of target expression dynamics for sequencing decisions. We critically appraise the evidence for target switching from HER2 to CLDN18.2, highlighting the mutual exclusivity of these targets and the critical gap posed by the exclusion of HER2-positive patients from most CLDN18.2 ADC trials. We further evaluate the role of dynamic re-biopsy and circulating tumor DNA (ctDNA) in real-time monitoring of target evolution. We propose a three-pillar decision-making framework integrating cross-resistance risk stratification, target landscape reassessment, and patient-clinician shared decision-making, accompanied by four practical sequencing scenarios. This framework is intended as a conceptual scaffold to guide clinical reasoning while awaiting the prospective trials urgently needed to establish evidence-based sequencing strategies in gastric adenocarcinoma.