leReal-world outcomes with front-line doublet versus triplet chemotherapy in advanced gastroesophageal adenocarcinoma.

313 Background: Current guidelines recommend an upfront cytotoxic doublet with or without targeted therapy or immunotherapy for the management of patients with advanced gastroesophageal adenocarcinoma (aGEA).While evidence for the superiority of combination chemotherapy over single agent chemotherapy has been well established, the comparison of two drug versus three drug regimens has been less definitive. This study analyzed a large real-world database to compare clinical outcomes between doublet and triplet approaches in the frontline setting. Methods: The nationwide de-identified Flatiron Health electronic health record (EHR)-derived database was reviewed for patients with aGEA treated with a first line (1L) cytotoxic doublet or triplet irrespective of combination targeted therapy between 2011 and 2022. Patients who received non-standard chemotherapy combinations or did not have a visit or medication order within 90 days of advanced stage diagnosis were excluded. Kaplan Meier and Cox proportional hazards models were used to compare overall survival outcomes between groups. Overall survival was considered as time from the 1L therapy to death with censoring for loss to follow up. Results: 5375 patients with aGEA who met inclusion criteria, 4415 (82%) received doublet chemotherapy and 960 (17%) received triplet in the 1L. Median OS (mOS) for those receiving a doublet was 11 months (95%CI 10-11) similar to those receiving a triplet (11 months, 95% CI 10-12). A Cox proportional hazards model controlling for potential confounding variables of gender, race, smoking status, disease site, as well as HER2 and PDL1 status did not show a significant difference in outcomes between the two groups (HR 0.9, 95%CI 0.8-1). A subgroup analysis comparing FLOT with FOLFOX/CapeOx demonstrated an improved mOS with FLOT (13 mo vs 10 mo; 95%CI 11-15 vs 9-10). This benefit was sustained in a multivariable analysis which demonstrated an increased risk of death with FOLFOX/CapeOX compared to FLOT (HR 1.2, 95% CI 1-1.4). Conclusions: Consistent with prior studies, this real-world study did not identify a significant difference in survival outcomes with 1L triplet compared to doublet chemotherapy in aGEA. When limiting analysis to modern chemotherapy regimens however this data does suggest that a survival benefit may exist with the use of FLOT when compared to FOFOX/CapeOX. This finding would need to be further evaluated in prospective trials incorporating immunotherapy and targeted therapy prior to widespread recommendation.