Objective To evaluate the efficacy and safety of tislelizumab added to chemotherapy as first line (primary) treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma compared with placebo plus chemotherapy. Design Randomised, double blind, placebo controlled, phase 3 study. Setting 146 medical centres across Asia, Europe, and North America, between 13 December 2018 and 28 February 2023. Participants 1657 patients aged ≥18 years with human epidermal growth factor receptor 2 negative locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma, regardless of programmed death-ligand 1 (PD-L1) expression status, who had not received systemic anticancer therapy for advanced disease. Interventions Patients were randomly (1:1) assigned to receive either tislelizumab 200 mg or placebo intravenously every three weeks in combination with chemotherapy (investigator’s choice of oxaliplatin and capecitabine, or cisplatin and 5-fluorouracil) and stratified by region, PD-L1 expression, presence or absence of peritoneal metastases, and investigator’s choice of chemotherapy. Treatment continued until disease progression or unacceptable toxicity. Main outcome measures The primary endpoint was overall survival, both in patients with a PD-L1 tumour area positivity (TAP) score of ≥5% and in all randomised patients. Safety was assessed in all those who received at least one dose of study treatment. Results Of 1657 patients screened between 13 December 2018 and 9 February 2021, 660 were ineligible due to not meeting the eligibility criteria, withdrawal of consent, adverse events, or other reasons. Overall, 997 were randomly assigned to receive tislelizumab plus chemotherapy (n=501) or placebo plus chemotherapy (n=496). Tislelizumab plus chemotherapy showed statistically significant improvements in overall survival versus placebo plus chemotherapy in patients with a PD-L1 TAP score of ≥5% (median 17.2 months v 12.6 months; hazard ratio 0.74 (95% confidence interval 0.59 to 0.94); P=0.006 (interim analysis)) and in all randomised patients (median 15.0 months v 12.9 months; hazard ratio 0.80 (0.70 to 0.92); P=0.001 (final analysis)). Grade 3 or worse treatment related adverse events were observed in 54% (268/498) of patients in the tislelizumab plus chemotherapy arm versus 50% (246/494) in the placebo plus chemotherapy arm. Conclusions Tislelizumab added to chemotherapy as primary treatment for advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma provided superior overall survival with a manageable safety profile versus placebo plus chemotherapy in patients with a PD-L1 TAP score of ≥5%, and in all randomised patients. Trial registration ClinicalTrials.gov [NCT03777657][1] On request, and subject to specific criteria, conditions, and exceptions, BeiGene will provide access to individual deidentified participant data from BeiGene sponsored global interventional clinical studies conducted for medicines for indications that have been approved, or in programmes that have been terminated. BeiGene will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data requests can be submitted to datadisclosure@beigene.com. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03777657&atom=%2Fbmj%2F385%2Fbmj-2023-078876.atom

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替雷利珠单抗加化疗与安慰剂加化疗作为晚期胃或胃食管交界腺癌的一线治疗：RATIONALE-305 随机、双盲、3 期试验


目的 评估与安慰剂加化疗相比，替雷利珠单抗联合化疗作为晚期胃或胃食管交界腺癌一线（主要）治疗的疗效和安全性。设计随机、双盲、安慰剂对照、3 期研究。 2018年12月13日至2023年2月28日期间，在亚洲、欧洲和北美的146个医疗中心进行研究。参与者1657名年龄≥18岁、患有人表皮生长因子受体2阴性、局部晚期不可切除或转移性胃或胃食管交界腺癌的患者，无论程序性死亡配体 1 (PD-L1) 表达状态如何，未接受针对晚期疾病的全身抗癌治疗的患者。干预措施 患者被随机 (1:1) 分配接受每三周静脉注射替雷利珠单抗 200 mg 或安慰剂联合化疗（研究者选择奥沙利铂和卡培他滨，或顺铂和 5-氟尿嘧啶），并按区域、PD-L1 表达进行分层、是否存在腹膜转移以及研究者选择的化疗方案。治疗持续直至疾病进展或出现不可接受的毒性。主要结局指标 主要终点是总体生存率，无论是 PD-L1 肿瘤面积阳性 (TAP) 评分≥5% 的患者还是所有随机分组的患者。对所有接受至少一剂研究治疗的患者进行安全性评估。结果 在2018年12月13日至2021年2月9日期间筛查的1657名患者中，有660名患者因不符合资格标准、撤回同意、不良事件或其他原因而不符合资格。总体而言，997 名患者被随机分配接受替雷利珠单抗加化疗 (n=501) 或安慰剂加化疗 (n=496)。 对于 PD-L1 TAP 评分≥5% 的患者，替雷利珠单抗联合化疗与安慰剂联合化疗相比，总生存期显着改善（中位时间 17.2 个月 vs 12.6 个月；风险比 0.74（95% 置信区间 0.59 至 0.94）；P= 0.006（中期分析））和所有随机患者（中位 15.0 个月 vs 12.9 个月；风险比 0.80（0.70 至 0.92）；P=0.001（最终分析））。替雷利珠单抗联合化疗组中 54% (268/498) 的患者观察到 3 级或更严重的治疗相关不良事件，而安慰剂加化疗组中这一比例为 50% (246/494)。结论 在 PD-L1 TAP 评分≥5% 的患者中，替雷利珠单抗联合化疗作为晚期或转移性胃或胃食管交界处腺癌的主要治疗，与安慰剂加化疗相比，可提供更好的总生存期，且安全性可控。患者。试验注册 ClinicalTrials.gov [NCT03777657][1] 根据要求，并根据具体标准、条件和例外情况，百济神州将提供来自百济神州赞助的针对已批准适应症的药物进行的全球干预临床研究的个人身份识别参与者数据的访问权限，或在已终止的程序中。百济神州还将考虑方案、数据字典和统计分析计划的请求。数据请求可提交至datadisclosure@beigene.com。 [1]：/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03777657&atom=%2Fbmj%2F385%2Fbmj-2023-078876。原子