The primary results of a randomized phase II trial of trifluridine/tipiracil (FTD/TPI) plus ramucirumab (RAM) versus FTD/TPI for previously treated patients with advanced gastric or gastroesophageal junction adenocarcinoma (RETRIEVE study, WJOG 15822G).

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357 Background: Trifluridine/tipiracil (FTD/TPI) has demonstrated survival benefit in the third- or later-line treatment for advanced gastric cancer (GC), gastroesophageal junction (GEJ) adenocarcinoma. Promising activity of FTD/TPI plus ramucirumab (RAM) has been reported in single-arm phase II trials for advanced GC or GEJ cancer; however, there have been no clinical trials to directly compare FTD/TPI plus RAM with FTD/TPI monotherapy in this setting. Methods: This is a multicenter, prospective, open-label, randomized phase II trial comparing FTD/TPI plus RAM versus FTD/TPI alone in patients with unresectable or recurrent GC or GEJ adenocarcinoma who were refractory or intolerant to fluoropyrimidine, taxane or irinotecan, and refractory (but not intolerant) to RAM. Key eligibility criteria include age of ≧20 years; ECOG performance status of 0 or 1; unresectable or recurrent gastric or GEJ adenocarcinoma, and at least a measurable lesion per RECIST 1.1. FTD/TPI (35 mg/m 2 twice daily, evening of day 1 to morning of day 6 and evening of day 8 to morning of day 13) was administered orally every 4 weeks, and RAM (8 mg/kg) was administered intravenously on day1 and 15 every 4 weeks. The primary endpoint is progression-free survival (PFS); the secondary endpoints are overall survival, objective response rate (ORR), disease control rate (DCR), and safety. The expected hazard ratio of PFS was set as 0.7 (power=70%, one-sided alpha=0.1) for the full analysis set, requiring 54 patients per arm. Results: From January 2023 to June 2024, 111 patients were randomly assigned to receive FTD/TPI plus RAM (n = 56) or FTD/TPI alone (n = 55). As of the data cutoff, 101 events for PFS were observed. The median PFS was 2.69 months in the combination arm and 2.07 months in the monotherapy arm, with a HR of 0.973 (80% CI, 0.749 to 1.264; P = 0.909). There was no significant difference in ORR (5.4% vs 9.1%, P = 0.489) and DCR (50.0% vs 47.3%, P = 0.850) between both arms. The most common adverse events (any grade) were neutropenia, anorexia, nausea, thrombocytopenia, and anemia across both groups. No novel safety signals were identified in both arms. The dose reduction was observed in 42.9% of FTD/TPI plus RAM and 32.7% of FTD/TPI alone. Conclusions: This is the first randomized trial to evaluate the addition of RAM to FTD/TPI in third- or later-line setting for advanced GC or GEJ adenocarcinoma. The combination did not demonstrate a significant improvement in PFS over FTD/TPI monotherapy. Clinical trial information: jRCTs041220120 .

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