Abstract：
BACKGROUND: 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.
METHODS: 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/m2) and cisplatin (25 mg/m2) 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 ClinicalTrials.gov, NCT03875235.
RESULTS: 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] vs 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%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%]).
CONCLUSIONS: 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.
BACKGROUND: AstraZeneca.
METHODS: 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/m2) and cisplatin (25 mg/m2) 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 ClinicalTrials.gov, NCT03875235.
RESULTS: 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] vs 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%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%]).
CONCLUSIONS: 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.
BACKGROUND: AstraZeneca.
摘要：
背景：在TOPAZ-1研究的预先计划的中期分析中，与安慰剂联合吉西他滨-顺铂相比,durvalumab联合吉西他滨-顺铂显著改善了晚期胆道癌参与者的总生存率.我们的目标是报告更新的TOPAZ-1的总生存期和安全性数据，并进行额外的随访和中期分析之外的数据成熟度。
方法：TOPAZ-1是第3阶段，随机，双面蒙面,安慰剂对照,在17个国家的105个地点进行的全球研究。18岁或以上不可切除的参与者，本地先进,或转移性胆道癌使用计算机生成的随机方案随机分配(1:1)至durvalumab联合吉西他滨-顺铂或安慰剂联合吉西他滨-顺铂,按疾病状态和原发肿瘤位置分层。参与者在每个周期的第1天接受durvalumab（1500mg）或安慰剂，每3周一次，持续8个周期。加吉西他滨（1000mg/m2）和顺铂（25mg/m2）在每个周期的第1天和第8天，每3周一次，最多8个周期，随后每4周接受Durvalumab(1500mg)或安慰剂单药治疗,直至疾病进展或其他停药标准得到满足.研究人员和参与者被掩盖以研究治疗。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其主要终点，这项研究很活跃，但不再招募参与者。更新了TOPAZ-1的总体生存和安全性数据，并进行了额外的随访（2022年2月25日数据截止）和中期分析后的数据成熟度，在这里报道。在完整分析集（所有随机分配的参与者）中评估疗效。在安全性分析集中评估安全性(接受至少一个剂量的研究治疗的所有参与者)。TOPAZ-1研究已在ClinicalTrials.gov注册，NCT03875235。
结果：从2019年4月16日至2020年12月11日，914名参与者被注册，其中685人被随机分配（341人被分配到durvalumab加吉西他滨-顺铂组，344人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。在更新数据截止时，durvalumab联合吉西他滨-顺铂组的中位随访时间为23·4个月(95%CI20·6-25·2)，安慰剂联合吉西他滨-顺铂组为22·4个月(21·4-23·8)。在更新的数据截止处，Durvalumab+吉西他滨-顺铂组248名（73%）参与者和安慰剂+吉西他滨-顺铂组279名（81%）参与者死亡（中位总生存期12·9个月[95%CI11·6-14·1]vs11·3个月[10·1-12·5]；风险比0·76[95%CI0·64-0·91]）。Kaplan-Meier估计的24个月总生存率在durvalumab加吉西他滨-顺铂组中为23·6％（95％CI18·7-28·9），在安慰剂加吉西他滨-顺铂组中为11·5％（7·6-16·2）。durvalumab加吉西他滨-顺铂组338名参与者中250名（74％）发生了最大的3级或4级不良事件，安慰剂加吉西他滨-顺铂组342名参与者中257名（75％）发生了最大的3级或4级不良事件。最常见的3级或4级治疗相关不良事件为中性粒细胞计数减少（70[21%]vs86[25%]）。贫血（64[19%]vs64[19%]），和中性粒细胞减少（63[19%]vs68[20%]）。
结论：Durvalumab联合吉西他滨-顺铂显示出稳健和持续的总体生存获益，没有新的安全性信号。研究结果继续支持该方案作为未经治疗的人的护理标准，晚期胆道癌.
背景：阿斯利康。
方法：TOPAZ-1是第3阶段，随机，双面蒙面,安慰剂对照,在17个国家的105个地点进行的全球研究。18岁或以上不可切除的参与者，本地先进,或转移性胆道癌使用计算机生成的随机方案随机分配(1:1)至durvalumab联合吉西他滨-顺铂或安慰剂联合吉西他滨-顺铂,按疾病状态和原发肿瘤位置分层。参与者在每个周期的第1天接受durvalumab（1500mg）或安慰剂，每3周一次，持续8个周期。加吉西他滨（1000mg/m2）和顺铂（25mg/m2）在每个周期的第1天和第8天，每3周一次，最多8个周期，随后每4周接受Durvalumab(1500mg)或安慰剂单药治疗,直至疾病进展或其他停药标准得到满足.研究人员和参与者被掩盖以研究治疗。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其主要终点，这项研究很活跃，但不再招募参与者。更新了TOPAZ-1的总体生存和安全性数据，并进行了额外的随访（2022年2月25日数据截止）和中期分析后的数据成熟度，在这里报道。在完整分析集（所有随机分配的参与者）中评估疗效。在安全性分析集中评估安全性(接受至少一个剂量的研究治疗的所有参与者)。TOPAZ-1研究已在ClinicalTrials.gov注册，NCT03875235。
结果：从2019年4月16日至2020年12月11日，914名参与者被注册，其中685人被随机分配（341人被分配到durvalumab加吉西他滨-顺铂组，344人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。在更新数据截止时，durvalumab联合吉西他滨-顺铂组的中位随访时间为23·4个月(95%CI20·6-25·2)，安慰剂联合吉西他滨-顺铂组为22·4个月(21·4-23·8)。在更新的数据截止处，Durvalumab+吉西他滨-顺铂组248名（73%）参与者和安慰剂+吉西他滨-顺铂组279名（81%）参与者死亡（中位总生存期12·9个月[95%CI11·6-14·1]vs11·3个月[10·1-12·5]；风险比0·76[95%CI0·64-0·91]）。Kaplan-Meier估计的24个月总生存率在durvalumab加吉西他滨-顺铂组中为23·6％（95％CI18·7-28·9），在安慰剂加吉西他滨-顺铂组中为11·5％（7·6-16·2）。durvalumab加吉西他滨-顺铂组338名参与者中250名（74％）发生了最大的3级或4级不良事件，安慰剂加吉西他滨-顺铂组342名参与者中257名（75％）发生了最大的3级或4级不良事件。最常见的3级或4级治疗相关不良事件为中性粒细胞计数减少（70[21%]vs86[25%]）。贫血（64[19%]vs64[19%]），和中性粒细胞减少（63[19%]vs68[20%]）。
结论：Durvalumab联合吉西他滨-顺铂显示出稳健和持续的总体生存获益，没有新的安全性信号。研究结果继续支持该方案作为未经治疗的人的护理标准，晚期胆道癌.
背景：阿斯利康。
