In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine–cisplatin significantly improved overall survival versus placebo plus gemcitabine–cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis. TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine–cisplatin or placebo plus gemcitabine–cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m) and cisplatin (25 mg/m) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with , . From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine–cisplatin group and 344 to the placebo plus gemcitabine–cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23·4 months (95% CI 20·6–25·2) in the durvalumab plus gemcitabine–cisplatin group and 22·4 months (21·4–23·8) in the placebo plus gemcitabine–cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine–cisplatin group and 279 (81%) participants in the placebo plus gemcitabine–cisplatin group had died (median overall survival 12·9 months [95% CI 11·6–14·1] 11·3 months [10·1–12·5]; hazard ratio 0·76 [95% CI 0·64–0·91]). Kaplan–Meier-estimated 24-month overall survival rates were 23·6% (95% CI 18·7–28·9) in the durvalumab plus gemcitabine–cisplatin group and 11·5% (7·6–16·2) in the placebo plus gemcitabine–cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine–cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine–cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] 86 [25%]), anaemia (64 [19%] 64 [19%]), and neutropenia (63 [19%] 68 [20%]). Durvalumab plus gemcitabine–cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer. AstraZeneca.

中文翻译：

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Durvalumab 或安慰剂加吉西他滨和顺铂治疗晚期胆道癌 (TOPAZ-1) 患者：随机 3 期研究的更新总生存期


在 TOPAZ-1 研究的预先计划中期分析中，与安慰剂加吉西他滨 - 顺铂相比，durvalumab 加吉西他滨 - 顺铂显着改善了晚期胆道癌参与者的总生存期。我们的目标是报告 TOPAZ-1 的最新总体生存和安全数据，并在中期分析之外进行额外的随访和数据成熟度。 TOPAZ-1 是一项 3 期、随机、双盲、安慰剂对照的全球研究，在 17 个国家的 105 个地点进行。使用计算机生成的随机化方案，将年龄 18 岁或以上患有不可切除的局部晚期或转移性胆道癌的参与者随机分配 (1:1) 至 durvalumab 加吉西他滨-顺铂或安慰剂加吉西他滨-顺铂，并按疾病状态和情况分层。原发肿瘤位置。参与者每 3 周在每个周期的第 1 天接受 durvalumab (1500 mg) 或安慰剂，最多 8 个周期，并在每个周期的第 1 天和第 8 天静脉注射吉西他滨 (1000 mg/m) 和顺铂 (25 mg/m) 3 周，最多 8 个周期，随后每 4 周进行一次 durvalumab（1500 mg）或安慰剂单药治疗，直至疾病进展或满足其他停药标准。研究人员和参与者对研究治疗不知情。主要终点是总生存期。 TOPAZ-1 在预先计划的中期分析中达到了主要终点，该研究正在进行中，但不再招募参与者。此处报告了 TOPAZ-1 的更新后总体生存率和安全性数据，以及额外的随访（数据截止日期为 2022 年 2 月 25 日）以及中期分析之外的数据成熟度。在完整的分析集中（所有随机分配的参与者）评估疗效。 在安全性分析组（所有接受至少一剂研究治疗的参与者）中评估安全性。 TOPAZ-1 研究已在 , 注册。从2019年4月16日到2020年12月11日，共招募了914名参与者，其中685名被随机分配（341名被分配到durvalumab加吉西他滨-顺铂组，344名被分配到安慰剂加吉西他滨-顺铂组）。 345 名 (50%) 参与者为男性，340 名 (50%) 为女性。更新数据截止点时，杜瓦鲁单抗加吉西他滨-顺铂组的中位随访时间为 23·4 个月（95% CI 20·6–25·2），而对照组为 22·4 个月（21·4–23·8）。安慰剂加吉西他滨-顺铂组。截至更新数据截止时，durvalumab 加吉西他滨-顺铂组的 248 名参与者 (73%) 和安慰剂加吉西他滨-顺铂组的 279 名参与者 (81%) 死亡（中位总生存期 12·9 个月 [95% CI 11] ·6–14·1] 11·3 个月 [10·1–12·5]；风险比 0·76 [95% CI 0·64–0·91]）。 Kaplan-Meier 估计的 durvalumab 加吉西他滨-顺铂组的 24 个月总生存率为 23·6% (95% CI 18·7–28·9) 和 11·5% (7·6–16·2)在安慰剂加吉西他滨-顺铂组中。最多 3 级或 4 级不良事件发生在 durvalumab 加吉西他滨-顺铂组的 338 名参与者中，有 250 名（74%）；安慰剂加吉西他滨-顺铂组的 342 名参与者中，有 257 名（75%）发生了 3 级或 4 级不良事件。最常见的最大 3 级或 4 级治疗相关不良事件是中性粒细胞计数减少 (70 [21%] 86 [25%])、贫血 (64 [19%] 64 [19%]) 和中性粒细胞减少 (63 [19%]) %] 68 [20%]）。 Durvalumab 联合吉西他滨-顺铂显示出强劲且持续的总体生存获益，且没有新的安全信号。研究结果继续支持该疗法作为未经治疗的晚期胆道癌患者的护理标准。阿斯利康。