Importance Trifluridine/tipiracil (FTD/TPI) treatment has shown clinical benefit in patients with pretreated metastatic gastric cancer or gastroesophageal junction cancer (mGC/GEJC). Patients who have undergone gastrectomy constitute a significant proportion of patients with mGC/GEJC.

Objective To assess the efficacy and safety of FTD/TPI among patients with previously treated mGC/GEJC who had or had not undergone gastrectomy.

Design, Setting, and Participants This preplanned subgroup analysis of TAGS (TAS-102 Gastric Study), a phase 3, randomized, placebo-controlled, clinical trial included patients with mGC/GEJC who had received at least 2 previous chemotherapy regimens, and was conducted at 110 academic hospitals in 17 countries in Europe, Asia, and North America, with enrollment between February 24, 2016, and January 5, 2018; the data cutoff was March 31, 2018.

Interventions Patients were randomized 2:1 to receive oral FTD/TPI 35 mg/m² twice daily or placebo twice daily with best supportive care on days 1 through 5 and days 8 through 12 of each 28-day treatment cycle.

Main Outcomes and Measures The primary end point was overall survival. This subgroup analysis was conducted to examine potential trends and was not powered for statistical significance. Efficacy and safety end points were evaluated in the subgroups.

Results Of 507 randomized patients (369 [72.8%] male; mean [SD] age, 62.5 [10.5] years), 221 (43.6%) had undergone gastrectomy (147 randomized to FTD/TPI and 74 to placebo) and 286 (56.4%) had not undergone gastrectomy (190 randomized to FTD/TPI and 96 to placebo). In the gastrectomy subgroup, the overall survival hazard ratio (HR) in the FTD/TPI group vs placebo group was 0.57 (95% CI, 0.41-0.79), and the progression-free survival HR was 0.48 (95% CI, 0.35-0.65). In the no gastrectomy subgroup, the overall survival HR in the FTD/TPI group vs placebo group was 0.80 (95% CI, 0.60-1.06), and the progression-free survival HR was 0.65 (95% CI, 0.49-0.85). Among FTD/TPI-treated patients, grade 3 or higher adverse events of any cause occurred in 122 of 145 patients (84.1%) in the gastrectomy subgroup and 145 of 190 (76.3%) in the no gastrectomy subgroup: 64 (44.1%) in the gastrectomy subgroup and 50 (26.3%) in the no gastrectomy subgroup had grade 3 or higher neutropenia, 31 (21.4%) in the gastrectomy subgroup and 33 (17.4%) in the no gastrectomy subgroup had grade 3 or higher anemia, and 21 (14.5%) in the gastrectomy subgroup and 10 (5.3%) in the no gastrectomy subgroup hD grade 3 or higher leukopenia. In the gastrectomy subgroup, 94 (64.8%) had dosing modifications because of adverse events vs 101 (53.2%) in the no gastrectomy subgroup; 15 (10.3%) in the gastrectomy group and 28 (14.7%) in the no gastrectomy group discontinued treatment because of adverse events. Treatment exposure was similar between groups.

Conclusions and Relevance The FTD/TPI treatment was tolerable and provided efficacy benefits among patients with pretreated mGC/GEJC regardless of previous gastrectomy.

Trial Registration ClinicalTrials.gov identifier: NCT02500043

重要性 曲氟尿苷/替吡嘧啶 (FTD/TPI) 治疗已显示出对预先治疗的转移性胃癌或胃食管结合部癌 (mGC/GEJC) 患者的临床益处。接受胃切除术的患者在 mGC/GEJC 患者中占很大比例。

目的 评估 FTD/TPI 在既往接受过或未接受过胃切除术的 mGC/GEJC 患者中的疗效和安全性。

设计、设置和参与者 这项预先计划的 TAGS 亚组分析（TAS-102 胃研究）是一项 3 期、随机、安慰剂对照的临床试验，纳入了之前接受过至少 2 次化疗方案的 mGC/GEJC 患者，并且是于 2016 年 2 月 24 日至 2018 年 1 月 5 日期间在欧洲、亚洲和北美 17 个国家的 110 家学术医院进行；数据截止日期为 2018 年 3 月 31 日。

干预 患者以 2:1 的比例随机接受口服 FTD/TPI 35 mg/m ²每日两次或安慰剂每日两次，在每个 28 天治疗周期的第 1 至 5 天和第 8 至 12 天接受最佳支持治疗。

主要结果和措施 主要终点是总生存期。进行该亚组分析是为了检查潜在趋势，并且没有统计学意义。在亚组中评估疗效和安全性终点。

结果 在 507 名随机患者中（369 名 [72.8%] 男性；平均 [SD] 年龄，62.5 [10.5] 岁），221 名（43.6%）接受了胃切除术（147 名随机接受 FTD/TPI，74 名接受安慰剂）和 286 名（56.4% ) 未接受胃切除术（190 人随机分配至 FTD/TPI，96 人随机分配至安慰剂组）。在胃切除术亚组中，FTD/TPI 组与安慰剂组的总生存风险比 (HR) 为 0.57 (95% CI, 0.41-0.79)，无进展生存 HR 为 0.48 (95% CI, 0.35- 0.65)。在无胃切除亚组中，FTD/TPI 组与安慰剂组的总生存期 HR 为 0.80（95% CI，0.60-1.06），无进展生存期 HR 为 0.65（95% CI，0.49-0.85）。在接受 FTD/TPI 治疗的患者中，胃切除术亚组的 145 名患者中有 122 人（84.1%）发生了 3 级或更高级别的任何原因不良事件，而无胃切除术亚组的 190 名患者中有 145 人（76.3%）发生了：64 人（44. 胃切除术亚组 1%) 和无胃切除术亚组 50 人 (26.3%) 有 3 级或更高级别的中性粒细胞减少，胃切除术亚组 31 人 (21.4%) 和无胃切除术亚组 33 人 (17.4%) 有 3 级或更高贫血，胃切除亚组中有 21 例（14.5%）和无胃切除亚组中有 10 例（5.3%）hD 3 级或更高级别的白细胞减少。在胃切除术亚组中，94 人（64.8%）因不良事件而进行了剂量调整，而未进行胃切除术亚组为 101 人（53.2%）；胃切除组15例（10.3%）和无胃切除组28例（14.7%）因不良事件停止治疗。各组之间的治疗暴露相似。无胃切除亚组中有 4%) 患有 3 级或更高级别的贫血，胃切除亚组中有 21 名 (14.5%) 和无胃切除亚组中有 10 名 (5.3%) 患有 3 级或更高级别的白细胞减少。在胃切除术亚组中，94 人（64.8%）因不良事件而进行了剂量调整，而未进行胃切除术亚组为 101 人（53.2%）；胃切除组15例（10.3%）和无胃切除组28例（14.7%）因不良事件停止治疗。各组之间的治疗暴露相似。无胃切除亚组中有 4%) 患有 3 级或更高级别的贫血，胃切除亚组中有 21 名 (14.5%) 和无胃切除亚组中有 10 名 (5.3%) 患有 3 级或更高级别的白细胞减少。在胃切除术亚组中，94 人（64.8%）因不良事件而进行了剂量调整，而未进行胃切除术亚组为 101 人（53.2%）；胃切除组15例（10.3%）和无胃切除组28例（14.7%）因不良事件停止治疗。各组之间的治疗暴露相似。7%）在无胃切除组中因不良事件而停止治疗。各组之间的治疗暴露相似。7%）在无胃切除组中因不良事件而停止治疗。各组之间的治疗暴露相似。

结论和相关性 FTD/TPI 治疗在接受过治疗的 mGC/GEJC 患者中是可以耐受的，并且无论之前是否进行了胃切除术，都可以提供疗效益处。

试验注册 ClinicalTrials.gov 标识符：NCT02500043