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Background  Platinum and fluoropyrimidine combinations typically comprise first‐line (1L) therapy in advanced gastric cancer or gastroesophageal junction adenocarcinoma (G/GEA), although controversy exists regarding the use of 5doublet versus triplet cytotoxic regimens. Historically, second‐line (2L) and third‐line or later (3L+) therapy has been fragmented. Recent trials have increased the need for optimal treatment sequencing in advanced G/GEA.    Materials and Methods  We conducted a systematic search of peer‐reviewed manuscripts of randomized clinical trials examining 1L, 2L, and 3L+ therapy for advanced G/GEA published from 2009 through November 19, 2019. When available, overall survival, progression‐free survival, time to progression, overall response rate, and toxicity were extracted from each and compared descriptively.    Results  In 1L therapy, chemotherapy triplets demonstrated variable efficacy improvements with invariable increased toxicity compared with platinum/fluoropyrimidine doublets. Currently, the only published report of positive outcomes using biologics in 1L describes adding trastuzumab in HER2‐overexpressing advanced G/GEA. In 2L, doublet chemotherapy regimens are not uniformly more efficacious than single‐agent taxanes or irinotecan, and ramucirumab has demonstrated improved outcomes both as monotherapy and in combination.    Conclusion  For advanced G/GEA, review of trial results from 2009–2019 support 1L therapy with platinum and fluoropyrimidine and sequencing with taxanes or irinotecan in combination with biologics as effective 2L options. Escalating to a triplet may add some efficacy at the expense of added toxicity.    Implications for Practice  The rapidly changing treatment landscape for advanced gastric cancer includes increasing options for refractory disease. With multiple first‐line platinum‐based regimens, identification of those with the best benefit‐to‐risk ratio may provide guidance on treatment sequencing strategies. This article presents findings from the published literature of randomized controlled trials that included a first‐line platinum/fluoropyrimidine combination and, for second‐line trials, patients with platinum/fluoropyrimidine‐refractory disease. This guiding summary could be a tool for clinicians to identify the optimal first‐line regimen(s) followed by a strategy for subsequent regimens.

Toward a Treatment Sequencing Strategy: A Systematic Review of Treatment Regimens in Advanced Gastric Cancer/Gastroesophageal Junction Adenocarcinoma