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纳武利尤单抗联合伊匹木单抗治疗晚期黑色素瘤的最终10年结局Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma本试验之前发表的结果显示，对于晚期黑色素瘤患者，纳武利尤单抗联合伊匹木单抗治疗或纳武利尤单抗单药治疗的总生存期超过伊匹木单抗单药治疗。鉴于晚期黑色素瘤患者的生存期已超过7.5年，因此需要收集更长期数据，以解答新的临床相关问题。Previous results from this trial showed longer overall survival after treatment with nivolumab plus ipilimumab or with nivolumab monotherapy than with ipilimumab monotherapy in patients with advanced melanoma. Given that patients with advanced melanoma are living longer than 7.5 years, longer-term data were needed to address new clinically relevant questions.我们以1:1:1比例将既往未接受过治疗的晚期黑色素瘤患者随机分配到以下治疗方案之一：每3周一次纳武利尤单抗（1 mg/kg体重）联合伊匹木单抗（3 mg/kg）（共4次），之后每2周一次纳武利尤单抗（3 mg/kg）；每2周一次纳武利尤单抗（3 mg/kg）联合安慰剂；或每3周一次伊匹木单抗（3 mg/kg）（共4次）联合安慰剂。治疗持续至疾病进展、出现不可接受的毒性效应或参与者撤回同意书。根据BRAF突变状态、转移灶分期和程序性死亡受体配体1表达情况进行分层随机化。本文报告此项试验的最终10年结果，包括总生存期和黑色素瘤特异性生存期以及缓解持久性。We randomly assigned patients with previously untreated advanced melanoma, in a 1:1:1 ratio, to one of the following regimens: nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks; nivolumab (3 mg per kilogram) every 2 weeks plus placebo; or ipilimumab (3 mg per kilogram) every 3 weeks for four doses plus placebo. Treatment was continued until the occurrence of disease progression, unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to BRAF mutation status, metastasis stage, and programmed death ligand 1 expression. Here, we report the final, 10-year results of this trial, including results for overall survival and melanoma-specific survival, as well as durability of response.经过至少10年随访中，纳武利尤单抗联合伊匹木单抗组的中位总生存期为71.9个月，纳武利尤单抗组为36.9个月，伊匹木单抗组为19.9个月。纳武利尤单抗联合伊匹木单抗组与伊匹木单抗组相比的死亡风险比为0.53（95%置信区间[CI]，0.44~0.65），纳武利尤单抗组与伊匹木单抗组相比的死亡风险比为0.63（95% CI，0.52~0.76）。纳武利尤单抗联合伊匹木单抗组的黑色素瘤特异性生存期超过120个月（未达到，试验结束时37%的患者仍存活），纳武利尤单抗组为49.4个月，伊匹木单抗组为21.9个月。在3年时仍存活且无进展的患者中，纳武利尤单抗联合伊匹木单抗组的10年黑色素瘤特异性生存率为96%，纳武利尤单抗组为97%，伊匹木单抗组为88%。With a minimum follow-up of 10 years, median overall survival was 71.9 months with nivolumab plus ipilimumab, 36.9 months with nivolumab, and 19.9 months with ipilimumab. The hazard ratio for death was 0.53 (95% confidence interval [CI], 0.44 to 0.65) for nivolumab plus ipilimumab as compared with ipilimumab and was 0.63 (95% CI, 0.52 to 0.76) for nivolumab as compared with ipilimumab. Median melanoma-specific survival was more than 120 months with nivolumab plus ipilimumab (not reached, with 37% of the patients alive at the end of the trial), 49.4 months with nivolumab, and 21.9 months with ipilimumab. Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97% with nivolumab, and 88% with ipilimumab.最终试验结果表明，对于晚期黑色素瘤患者，与伊匹木单抗单药治疗相比，纳武利尤单抗联合伊匹木单抗治疗和纳武利尤单抗单药治疗持续带来生存获益。（由百时美施贵宝等公司资助；CheckMate 067在ClinicalTrials.gov注册号为NCT01844505）The final trial results showed a continued, ongoing survival benefit with nivolumab plus ipilimumab and with nivolumab monotherapy, as compared with ipilimumab monotherapy, in patients with advanced melanoma. (Funded by Bristol Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.)Jedd D. Wolchok, Vanna Chiarion-Sileni, Piotr Rutkowski, et al. Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma. DOI: 10.1056/NEJMoa2407417
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心房颤动患者接受asundexian与阿哌沙班治疗的比较
Asundexian versus Apixaban in Patients with Atrial Fibrillation
心房颤动患者使用直接作用的口服抗凝剂预防卒中有出血风险，因此限制了其用药。活化因子XI（XIa）抑制剂asundexian是一种可预防卒中且出血较少的口服抗凝剂。Stroke prevention with direct-acting oral anticoagulant agents in patients with atrial fibrillation confers a risk of bleeding and limits their use. Asundexian, an activated factor XI (XIa) inhibitor, is an oral anticoagulant that may prevent strokes with less bleeding.在一项3期、国际性、双盲试验中，我们以1:1比例随机分配患心房颤动的高危患者接受每日一次50 mg asundexian治疗或标准剂量阿哌沙班治疗。主要疗效目标是确定在预防卒中或体循环栓塞方面，apixaban是否至少不劣于阿哌沙班。主要安全性目标是确定在大出血事件方面，asundexian是否优于阿哌沙班。In a phase 3, international, double-blind trial, we randomly assigned high-risk patients with atrial fibrillation in a 1:1 ratio to receive asundexian at a dose of 50 mg once daily or standard-dose apixaban. The primary efficacy objective was to determine whether asundexian is at least noninferior to apixaban for the prevention of stroke or systemic embolism. The primary safety objective was to determine whether asundexian is superior to apixaban with respect to major bleeding events.共计14,810例随机分组患者被纳入意向性治疗人群。患者的平均（±SD）年龄为73.9±7.7岁，35.2%为女性，18.6%患慢性肾病，18.2%曾发生过卒中或短暂性脑缺血发作，16.8%接受过不超过6周口服抗凝剂治疗，平均CHA2DS2-VASc评分（范围，0~9，评分较高表示卒中风险较大）为4.3±1.3分。根据独立数据监查委员会的建议，试验被提前终止。asundexian组98例患者（1.3%）和阿哌沙班组26例患者（0.4%）发生了卒中或体循环栓塞（风险比，3.79；95%置信区间[CI]，2.46~5.83）。asundexian组17例患者（0.2%）和阿哌沙班组53例患者（0.7%）发生了大出血（风险比，0.32；95% CI，0.18~0.55）。两组的不良事件发生率似乎相似。A total of 14,810 randomly assigned patients were included in the intention-to-treat population. The mean (±SD) age of the patients was 73.9±7.7 years, 35.2% were women, 18.6% had chronic kidney disease, 18.2% had a previous stroke or transient ischemic attack, 16.8% had received oral anticoagulants for no more than 6 weeks, and the mean CHA2DS2-VASc score (range, 0 to 9, with higher scores indicating a greater risk of stroke) was 4.3±1.3. The trial was stopped prematurely at the recommendation of the independent data monitoring committee. Stroke or systemic embolism occurred in 98 patients (1.3%) assigned to receive asundexian and in 26 (0.4%) assigned to receive apixaban (hazard ratio, 3.79; 95% confidence interval [CI], 2.46 to 5.83). Major bleeding occurred in 17 patients (0.2%) who received asundexian and in 53 (0.7%) who received apixaban (hazard ratio, 0.32; 95% CI, 0.18 to 0.55). The incidence of any adverse event appeared to be similar in the two groups.在有卒中风险的心房颤动患者中，在试验提前终止前的一段时间内，每日一次50 mg asundexian组的卒中或体循环栓塞发生率高于阿哌沙班组。在此期间，asundexian组的大出血事件发生率低于阿哌沙班组。（由拜耳公司资助；OCEANIC-AF在ClinicalTrials.gov注册号为NCT05643573；EudraCT编号为2022-000758-28）。Among patients with atrial fibrillation at risk for stroke, treatment with asundexian at a dose of 50 mg once daily was associated with a higher incidence of stroke or systemic embolism than treatment with apixaban in the period before the trial was stopped prematurely. There were fewer major bleeding events with asundexian than with apixaban during this time. (Funded by Bayer; OCEANIC-AF ClinicalTrials.gov number, NCT05643573; EudraCT number, 2022-000758-28.)Jonathan P. Piccini, Manesh R. Patel, Jan Steffel, et al.Asundexian versus Apixaban in Patients with Atrial Fibrillation. DOI:10.1056/NEJMoa2407105
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vutrisiran治疗转甲状腺素蛋白淀粉样变性伴心肌病试验Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy转甲状腺素蛋白淀粉样变性伴心肌病（ATTR-CM）是一种不断进展的致死性疾病。vutrisiran是皮下注射的RNA干扰治疗剂，可抑制肝脏内转甲状腺素的生成。Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, fatal disease. Vutrisiran, a subcutaneously administered RNA interference therapeutic agent, inhibits the production of hepatic transthyretin.
在此项双盲随机试验中，我们以1:1比例分配ATTR-CM患者接受vutrisiran（25 mg）或安慰剂治疗，每12周一次，最长持续36个月。主要终点是由全因死亡和复发性心血管事件构成的复合终点。次要终点包括全因死亡、6分钟步行距离与基线相比的变化，以及堪萨斯城心肌病问卷总分（KCCQ-OS，Kansas City Cardiomyopathy Questionnaire– Overall Summary）与基线相比的变化。疗效终点在总体人群和单药治疗人群（基线时未接受tafamidis治疗的患者）中评估，并进行序贯检验。In this double-blind, randomized trial, we assigned patients with ATTR-CM in a 1:1 ratio to receive vutrisiran (25 mg) or placebo every 12 weeks for up to 36 months. The primary end point was a composite of death from any cause and recurrent cardiovascular events. Secondary end points included death from any cause, the change from baseline in the distance covered on the 6-minute walk test, and the change from baseline in the Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS) score. The efficacy end points were assessed in the overall population and in the monotherapy population (the patients who were not receiving tafamidis at baseline) and were tested hierarchically.共计655例患者接受了随机分组，其中326人被分配接受vutrisiran治疗，329人被分配接受安慰剂治疗。vutrisiran与安慰剂相比降低了42个月时的全因死亡和复发性心血管事件风险（总体人群中的风险比，0.72；95%置信区间[CI]，0.56~0.93；P=0.01；单药治疗人群中的风险比，0.67；95% CI，0.49~0.93；P=0.02），也降低了全因死亡风险（总体人群中的风险比，0.65；95% CI，0.46~0.90；P=0.01）。在总体人群中，vutrisiran组125例患者和安慰剂组159例患者发生了至少一起主要终点事件。在总体人群中，vutrisiran与安慰剂相比减小了6分钟步行距离的缩短幅度（最小二乘平均差异，26.5 m；95% CI，13.4~39.6；P<0.001），也减小了KCCQ-OS评分下降幅度（最小二乘平均差异，5.8分；95% CI，2.4~9.2；P<0.001）。在单药治疗人群中也观察到类似益处。两组的不良事件发生率相似（vutrisiran组99%，安慰剂组98%）；vutrisiran组严重不良事件发生率为62%，安慰剂组为67%。A total of 655 patients underwent randomization; 326 were assigned to receive vutrisiran and 329 to receive placebo. Vutrisiran treatment led to a lower risk of death from any cause and recurrent cardiovascular events than placebo (hazard ratio in the overall population, 0.72; 95% confidence interval [CI], 0.56 to 0.93; P=0.01; hazard ratio in the monotherapy population, 0.67; 95% CI, 0.49 to 0.93; P=0.02) and a lower risk of death from any cause through 42 months (hazard ratio in the overall population, 0.65; 95% CI, 0.46 to 0.90; P=0.01). Among the patients in the overall population, 125 in the vutrisiran group and 159 in the placebo group had at least one primary end-point event. In the overall population, treatment with vutrisiran resulted in less of a decline in the distance covered on the 6-minute walk test than placebo (least-squares mean difference, 26.5 m; 95% CI, 13.4 to 39.6; P<0.001) and less of a decline in the KCCQ-OS score (least-squares mean difference, 5.8 points; 95% CI, 2.4 to 9.2; P<0.001). Similar benefits were observed in the monotherapy population. The incidence of adverse events was similar in the two groups (99% in the vutrisiran group and 98% in the placebo group); serious adverse events occurred in 62% of the patients in the vutrisiran group and in 67% of those in the placebo group.在ATTR-CM患者中，与安慰剂相比，vutrisiran治疗可降低全因死亡和心血管事件风险，并有助于患者保持功能能力和生活质量。（由Alnylam Pharmaceuticals资助；HELIOS-B在ClinicalTrials.gov注册号为NCT04153149）。Among patients with ATTR-CM, treatment with vutrisiran led to a lower risk of death from any cause and cardiovascular events than placebo and preserved functional capacity and quality of life. (Funded by Alnylam Pharmaceuticals; HELIOS-B ClinicalTrials.gov number, NCT04153149.)Marianna Fontana, John L. Berk, Julian D. Gillmore, et al. Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy. DOI: 10.1056/NEJMoa2409134
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肌层浸润性尿路上皮癌接受帕博利珠单抗辅助治疗与观察的比较Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma肌层浸润性尿路上皮癌是一种侵袭性疾病，复发率很高。帕博利珠单抗辅助治疗对根治术后的高危肌层浸润性尿路上皮癌患者是否有效，目前尚不清楚。Muscle-invasive urothelial carcinoma is an aggressive disease with high rates of relapse. Whether pembrolizumab as adjuvant therapy would be effective in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery is unknown.在此项3期试验中，我们以1:1比例随机分配患者接受帕博利珠单抗治疗（剂量为每3周200 mg，为期1年）或接受观察。根据病理分期、集中检测的程序性死亡受体配体1（PD-L1）状态和既往新辅助化疗情况进行分层随机化。联合主要终点是意向性治疗人群的无病生存期和总生存期。如果帕博利珠单抗组的无病生存期或总生存期显著超过观察组，则认为试验成功。In this phase 3 trial, we randomly assigned patients, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks for 1 year or to undergo observation. Randomization was stratified according to pathological stage, centrally tested programmed death ligand 1 (PD-L1) status, and previous neoadjuvant chemotherapy. The coprimary end points were disease-free survival and overall survival in the intention-to-treat population. We considered the trial to be successful if either disease-free survival or overall survival was significantly longer with pembrolizumab than with observation.共计702例患者接受了随机分组，其中354人被分配接受帕博利珠单抗治疗，348人被分配接受观察。截至2024年7月5日，无病生存期中位随访时间为44.8个月。帕博利珠单抗组的中位无病生存期为29.6个月（95%置信区间[CI]，20.0~40.7），而观察组为14.2个月（95% CI，11.0~20.2）（疾病进展或死亡的风险比，0.73；95% CI，0.59~0.90；双侧P=0.003）。帕博利珠单抗组50.7%的患者和观察组31.6%的患者发生了3级或更高级别不良事件（不考虑原因）。A total of 702 patients underwent randomization; 354 were assigned to receive pembrolizumab, and 348 were assigned to observation. As of July 5, 2024, the median duration of follow-up for disease-free survival was 44.8 months. The median disease-free survival was 29.6 months (95% confidence interval [CI], 20.0 to 40.7) with pembrolizumab and 14.2 months (95% CI, 11.0 to 20.2) with observation (hazard ratio for disease progression or death, 0.73; 95% CI, 0.59 to 0.90; two-sided P=0.003). Grade 3 or higher adverse events (regardless of attribution) occurred in 50.7% of the patients in the pembrolizumab group and in 31.6% of the patients in the observation group.在根治术后的高危肌层浸润性尿路上皮癌患者中，接受帕博利珠单抗辅助治疗的无病生存期显著超过接受观察。（由美国国立卫生研究院国家癌症研究所等资助；Alliance A031501 AMBASSADOR在ClinicalTrials.gov注册号为NCT03244384）。Among patients with high-risk muscle-invasive urothelial carcinoma after radical surgery, disease-free survival was significantly longer with adjuvant pembrolizumab than with observation. (Funded by the National Cancer Institute of the National Institutes of Health and others; Alliance A031501 AMBASSADOR ClinicalTrials.gov number, NCT03244384.).Andrea B. Apolo, Karla V. Ballman, Guru Sonpavde, et al. Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma. DOI: 10.1056/NEJMoa2401726![]()
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