George, Ben

399 Background: The standard of care for resectable GEA adenocarcinomas is perioperative chemotherapy with the FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel) regimen. Recent studies investigating the addition of checkpoint inhibitors (CPIs) to perioperative chemotherapy have shown mixed results. An NMA can leverage both direct and indirect comparisons to evaluate the relative efficacies of available regimens in this setting. Methods: MEDLINE, EMBASE, Scopus, Web of Science and CENTRAL were searched until August 27th, 2025. Eligible studies included phase 3 randomized trials evaluating perioperative or neoadjuvant chemotherapy +/- CPIs ± radiation in resectable GEA. The primary outcomes were disease-free survival (DFS) and overall survival (OS). Hazard ratios and 95% confidence intervals (CIs) were estimated using a frequentist NMA framework. Results: Fifteen trials including 8072 patients were analyzed. For DFS, perioperative durvalumab + FLOT (dFLOT) ranked highest (P-score = 0.99), followed by FLOT (P-score = 0.84) (HR for dFLOT vs. FLOT was 0.71, 95% CI 0.58-0.86). dFLOT also ranked higher than perioperative pembrolizumab + cisplatin and fluorouracil/capecitabine (KN-585), though this comparison was not statistically significant (HR 0.65, 95% CI 0.40-1.04). Compared with CROSS, dFLOT showed superior DFS (HR of 0.48, 95% CI 0.36-0.63). For OS, dFLOT ranked the highest (P-score=0.95) and was superior to CROSS (HR 0.57, 95% CI 0.42-0.77). While dFLOT appeared favorable versus FLOT (HR 0.78, 95% CI 0.62-0.98), this finding was primarily driven by MATTERHORN, which did not meet its prespecified OS significance boundary (P = 0.03 vs threshold P < 0.0001), and the proportional hazards assumption was violated. Similarly, no significant OS difference was observed between dFLOT and the KN-585 arms (HR 0.75, 95% CI 0.45-1.23). Conclusions: In this NMA, perioperative FLOT remained the benchmark regimen for resectable GEA. dFLOT has shown promising early results, ranking the highest for DFS and showing favorable, but not statistically definitive OS trends in comparison to FLOT. Importantly, the network enabled indirect comparisons not tested in head-to-head trials, demonstrating that dFLOT ranked above pembrolizumab+CF/CX (KN-585) without reaching statistical significance, and also outperformed CROSS. However, these findings should be interpreted with caution, as they are primarily driven MATTERHORN data in which OS did not cross the prespecified threshold and proportional hazards assumptions were violated. Perioperative immunotherapy combinations appear promising, but final MATTERHORN results and further confirmatory studies are needed before dFLOT can be considered as a new standard of care.

Background/objectives: Improvements in esophageal adenocarcinoma (EAC) treatment have reduced mortality. While chemoradiation before surgery was previously a standard of care, updated guidelines recommend peri-operative chemotherapy without chemoradiation. Continued investigation into optimal non-operative treatment paradigms for patients who defer surgery or are not candidates for surgery and certain chemotherapy regimens is needed. The impact of induction chemotherapy prior to chemoradiation on survival and surgical outcomes remains unclear. This study assessed survival and surgical outcomes in a real-world cohort of EAC patients receiving induction chemotherapy before chemoradiation. Methods: This single-institution, IRB-approved, retrospective cohort study included patients with newly diagnosed stage II-IVb (oligometastatic for IVb) EAC who received definitive chemoradiation (radiation ≥ 40 Gy and two cycles of chemotherapy) +/− esophagectomy from 2007 to 2022. Patients receiving induction chemotherapy were compared to those who did not. Endpoints included survival and surgical outcomes. Results: A total of 141 EAC patients received definitive chemoradiation; 83 received induction chemotherapy before chemoradiation. Patients receiving induction chemotherapy were younger (p < 0.01) with slightly lower performance status (p = 0.27) and presented at a more advanced stage (p < 0.001). Median OS was 3.5 years in the induction chemotherapy group compared to 2.2 years (p = 0.10). There was no difference in pathologic complete response (p = 0.81), esophagectomy frequency (p = 0.87), or surgical downstaging between treatment groups (p = 0.84). Conclusions: In this real-world, single-institutional patient cohort investigating induction chemotherapy prior to chemoradiation in EAC, patients receiving induction chemotherapy did well but did not have a statistically significant improvement in survival outcomes or surgical outcomes. This study showed that significant numbers of real-world patients may not receive esophagectomy. Thus, prospective, randomized clinical trials are warranted to better delineate the efficacy and selection of patients for induction chemotherapy when non-operative approaches are favored.