Future of Perioperative IO + FLOT Chemotherapy in GC/GEJC

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The role of perioperative IO in gastric cancers (GC) and gastroesophageal cancers (GEJC) appears solidified and will likely expand further as the foundation for future therapeutic development. Although awaiting mature overall survival data would provide the ideal “1-2 punch” of positive event-free survival and overall survival end points, the current evidence already establishes D-FLOT as a clear standard of care. The promising appearance of early overall survival curves generates optimism for eventual positive results, which would further reinforce this therapeutic approach. Rather than questioning whether perioperative therapy can be eliminated or simplified, future research will focus on building upon this established foundation to achieve even better outcomes.

Future directions will likely emphasize biomarker-driven personalization of perioperative therapy, incorporating emerging targeted agents, antibody-drug conjugates, and bispecific antibodies as they prove effective in metastatic disease settings. The integration of novel anti-HER2 therapies, such as those presented with trastuzumab deruxtecan in metastatic disease, represents an exciting potential addition to perioperative regimens. Personalized treatment approaches based on tumor biology and genomic characteristics may allow for substitution of FLOT components with more targeted, less toxic alternatives while maintaining or improving efficacy.

Several important clinical questions emerge from MATTERHORN’s success, including whether adjuvant FLOT is necessary or whether extended IO alone might suffice, potentially guided by circulating tumor DNA or other biomarkers. The possibility of delivering all therapy in the neoadjuvant setting rather than splitting treatment before and after surgery represents another area of investigation. Perhaps most aspirationally, the goal of organ preservation for selected patients, particularly those with microsatellite instability–high tumors who achieve complete responses, represents an exciting future direction. However, organ-sparing approaches should remain within clinical trial settings for microsatellite-stable tumors until appropriate tools for accurate disease assessment are validated and standardized.