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Abstract：
BACKGROUND: We evaluated whether the addition of docetaxel (D) to a combination comprising 5-fluorouracil/leucovorin (5-FU/LV) or capecitabine (C) plus oxaliplatin (O) (DOF/DOX) improved overall survival (OS) compared with 6 months of 5-fluorouracil (5-FU) or capecitabine in combination with oxaliplatin (FOLFOX/CAPOX) alone in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas (G/GEJ).
METHODS: This study was an investigator-initiated, open-label, multi-institutional, randomized phase III trial in adult patients with HER2-negative advanced G/GEJs. The primary endpoint of the study was a comparison of median OS by Kaplan-Meier method. Next-generation sequencing was performed on tissue.
RESULTS: Of the 324 patients randomly assigned between July 2020 and November 2022, 305 patients were evaluable for analysis (FOLFOX/CAPOX: 156; DOF/DOX: 149). With a median follow-up time of 19.2 months (95% Confidence Interval [CI] = 16.5 months to 21.9 months) for the entire cohort, the median OS was 10.1 months (95% CI = 9.2 to 10.9) for FOLFOX/CAPOX and 8.9 months (95% CI = 7.3 to 10.5) for DOF/DOX, and this difference was not statistically significant (P = .70). An increased proportion of grade 3 or grade 4 neutropenia (21% vs 3%; P < .001) and grade 2/3 neuropathy (17% vs 7%; P = .005) was seen in patients receiving DOF/DOX. Genomic profiling revealed a low incidence of microsatellite instability (1%) and a high incidence of BRCA1 (8.4%) and BRCA2 (7.5%) somatic alterations.
CONCLUSIONS: FOLFOX or CAPOX chemotherapy for 6 months remains one of the standards of care in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas, with no additional survival benefit seen with the addition of docetaxel. Genomic profiling of patients revealed a higher than previously known incidence of somatic BRCA alterations, which requires further evaluation.CTRI (Clinical Trial Registry of India: CTRI/2020/03/023944).
METHODS: This study was an investigator-initiated, open-label, multi-institutional, randomized phase III trial in adult patients with HER2-negative advanced G/GEJs. The primary endpoint of the study was a comparison of median OS by Kaplan-Meier method. Next-generation sequencing was performed on tissue.
RESULTS: Of the 324 patients randomly assigned between July 2020 and November 2022, 305 patients were evaluable for analysis (FOLFOX/CAPOX: 156; DOF/DOX: 149). With a median follow-up time of 19.2 months (95% Confidence Interval [CI] = 16.5 months to 21.9 months) for the entire cohort, the median OS was 10.1 months (95% CI = 9.2 to 10.9) for FOLFOX/CAPOX and 8.9 months (95% CI = 7.3 to 10.5) for DOF/DOX, and this difference was not statistically significant (P = .70). An increased proportion of grade 3 or grade 4 neutropenia (21% vs 3%; P < .001) and grade 2/3 neuropathy (17% vs 7%; P = .005) was seen in patients receiving DOF/DOX. Genomic profiling revealed a low incidence of microsatellite instability (1%) and a high incidence of BRCA1 (8.4%) and BRCA2 (7.5%) somatic alterations.
CONCLUSIONS: FOLFOX or CAPOX chemotherapy for 6 months remains one of the standards of care in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas, with no additional survival benefit seen with the addition of docetaxel. Genomic profiling of patients revealed a higher than previously known incidence of somatic BRCA alterations, which requires further evaluation.CTRI (Clinical Trial Registry of India: CTRI/2020/03/023944).
摘要：
目的：我们评估了在包含5-氟尿嘧啶/亚叶酸钙（5-FU/LV）或卡培他滨（C）加奥沙利铂（O）（DOF/DOX）的组合中添加多西他赛（D）在晚期HER2阴性胃-GEJ连接和胃腺癌中，与单独使用FOLFOX/CAPOX相比，可改善总生存期（OS）
方法：本研究由研究者发起，开放标签，多机构，在HER2阴性的晚期GEJ/GC成年患者中进行的随机III期试验。研究的主要终点是通过Kaplan-Meier方法比较中位OS。对组织进行下一代测序。
结果：在2020年7月至2022年11月之间随机分配的324例患者中，有305例患者可进行评估分析（FOLFOX/CAPOX：156；DOF/DOX：149）。整个队列的中位随访时间为19.2个月（95％CI：16.5-21.9），FOLFOX/CAPOX的中位OS为10.1个月(95%:9.2-10.9),DOF/DOX的中位OS为8.9个月(95%CI:7.3-10.5),这一差异无统计学意义[p=.70].在接受DOF/DOX的患者中，3/4级中性粒细胞减少症（21％vs3％；p<.001）和2/3级神经病变（17％vs7％；p=.005）的比例增加。基因组分析显示，微卫星不稳定性的发生率较低（1％），而BRCA1（7.5％）和BRCA2（8.4％）体细胞改变的发生率较高。
结论：FOLFOX或CAPOX化疗6个月仍然是晚期HER2阴性胃食管交界处和胃腺癌的治疗标准之一，添加多西他赛没有额外的生存益处。患者的基因组分析显示，体细胞BRCA改变的发生率高于先前已知的发生率，需要进一步评估。
方法：本研究由研究者发起，开放标签，多机构，在HER2阴性的晚期GEJ/GC成年患者中进行的随机III期试验。研究的主要终点是通过Kaplan-Meier方法比较中位OS。对组织进行下一代测序。
结果：在2020年7月至2022年11月之间随机分配的324例患者中，有305例患者可进行评估分析（FOLFOX/CAPOX：156；DOF/DOX：149）。整个队列的中位随访时间为19.2个月（95％CI：16.5-21.9），FOLFOX/CAPOX的中位OS为10.1个月(95%:9.2-10.9),DOF/DOX的中位OS为8.9个月(95%CI:7.3-10.5),这一差异无统计学意义[p=.70].在接受DOF/DOX的患者中，3/4级中性粒细胞减少症（21％vs3％；p<.001）和2/3级神经病变（17％vs7％；p=.005）的比例增加。基因组分析显示，微卫星不稳定性的发生率较低（1％），而BRCA1（7.5％）和BRCA2（8.4％）体细胞改变的发生率较高。
结论：FOLFOX或CAPOX化疗6个月仍然是晚期HER2阴性胃食管交界处和胃腺癌的治疗标准之一，添加多西他赛没有额外的生存益处。患者的基因组分析显示，体细胞BRCA改变的发生率高于先前已知的发生率，需要进一步评估。
