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作者：NEJM医学前沿
英文音频来自NEJM官网nejm.org
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阿来替尼治疗切除术后ALK阳性非小细胞肺癌试验
Alectinib in Resected ALK-Positive Non–Small-Cell Lung Cancer
摘 要
背景
铂类化疗是可切除ALK阳性非小细胞肺癌（NSCLC）患者的推荐辅助治疗。与化疗相比，阿来替尼辅助治疗对于切除术后ALK阳性NSCLC患者的疗效和安全性尚缺乏相关数据。
Background
Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non–small-cell lung cancer (NSCLC). Data on the efficacy and safety of adjuvant alectinib as compared with chemotherapy in patients with resected ALK-positive NSCLC are lacking.
方法
我们开展了一项全球性、3期、开放标签、随机试验，该试验将完全切除术后ALK阳性ⅠB期（肿瘤≥4 cm）、Ⅱ期或IIIA期NSCLC患者（根据美国癌症联合委员会[American Joint Committee on Cancer]和国际癌症控制联盟[Union for International Cancer Control]的《癌症分期手册》[Cancer Staging Manual]第七版进行分类）以1:1比例随机分成两组，分别口服阿来替尼（每天两次，每次600 mg）24个月或静脉注射铂类化疗4个周期（每个周期21天）。主要终点是无病生存期，在Ⅱ期或IIIA期患者中进行分级检验，之后在意向性治疗人群中进行检验。其他终点包括中枢神经系统（CNS）无病生存期、总生存期和安全性。
Methods
We conducted a global, phase 3, open-label, randomized trial in which patients with completely resected, ALK-positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA (as classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer and Union for International Cancer Control) were randomly assigned in a 1:1 ratio to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was disease-free survival, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat population. Other end points included central nervous system (CNS) disease–free survival, overall survival, and safety.
结果
共计257例患者被随机分配接受阿来替尼（130例）或化疗（127例）。在Ⅱ期或IIIA期疾病患者中，阿来替尼组的2年无病生存率为93.8%，化疗组为63.0%（疾病复发或死亡的风险比，0.24；95%置信区间[CI]，0.13~0.45；P<0.001）；在意向性治疗人群中，两组的2年无病生存率分别为93.6%和63.7%（风险比，0.24；95% CI，0.13~0.43；P<0.001）。与化疗相比，阿来替尼在CNS无病生存率方面与有临床意义的益处相关（CNS疾病复发或死亡的风险比，0.22；95% CI，0.08~0.58）。总生存率数据尚不成熟。本试验中没有非预期的安全性结果。
Result
In total, 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (hazard ratio for disease recurrence or death, 0.24; 95% confidence interval [CI], 0.13 to 0.45; P<0.001) and 93.6% and 63.7%, respectively, in the intention-to-treat population (hazard ratio, 0.24; 95% CI, 0.13 to 0.43; P<0.001). Alectinib was associated with a clinically meaningful benefit with respect to CNS disease–free survival as compared with chemotherapy (hazard ratio for CNS disease recurrence or death, 0.22; 95% CI, 0.08 to 0.58). Data for overall survival were immature. No unexpected safety findings were observed.
结论
在切除术后ALK阳性ⅠB期、Ⅱ期或IIIA期NSCLC患者中，与铂类化疗相比，阿来替尼辅助治疗显著提高无病生存率。（由罗氏公司资助；ALINA在ClinicalTrials.gov注册号为NCT03456076）。
Conclusions
Among patients with resected ALK-positive NSCLC of stage IB, II, or IIIA, adjuvant alectinib significantly improved disease-free survival as compared with platinum-based chemotherapy. (Funded by F. Hoffmann–La Roche; ALINA ClinicalTrials.gov number, NCT03456076.)
Yi-Long Wu, Rafal Dziadziuszko, Jin Seok Ahn, et al. Alectinib in Resected ALK-Positive Non–Small-Cell Lung Cancer.DOI:10.1056/NEJMoa2310532本周五 中午十二点 app和官网发布全文中译2
脑出血早期微创清除术试验
Trial of Early Minimally Invasive Removal of Intracerebral Hemorrhage
摘 要
背景
幕上脑出血的清除术试验一般显示对功能并无益处。早期微创清除术可否实现优于药物治疗的结局，目前尚不清楚。
BackgroundTrials of surgical evacuation of supratentorial intracerebral hemorrhages have generally shown no functional benefit. Whether early minimally invasive surgical removal would result in better outcomes than medical management is not known.
方法
在此项纳入急性脑出血患者的多中心随机试验中，我们比较了血肿清除术与药物治疗。在发生脑叶或前基底神经节出血，血肿体积30~80 mL，并且最后已知状况良好的时间在24小时内的患者中，我们以1:1比例将其分成两组，分别接受血肿微创清除术联合基于指南的药物治疗（手术组）或单纯接受基于指南的药物治疗（对照组）。主要疗效终点是180天时的效用加权改良Rankin量表（modified Rankin scale）（范围，0~1，根据患者的评估，评分较高表示结局较好）平均评分，预设的优效性后验概率阈值为≥0.975。试验包括根据出血部位调整纳入标准的规则。主要安全性终点是纳入试验后30天内死亡。
Methods
In this multicenter, randomized trial involving patients with an acute intracerebral hemorrhage, we assessed surgical removal of the hematoma as compared with medical management. Patients who had a lobar or anterior basal ganglia hemorrhage with a hematoma volume of 30 to 80 ml were assigned, in a 1:1 ratio, within 24 hours after the time that they were last known to be well, to minimally invasive surgical removal of the hematoma plus guideline-based medical management (surgery group) or to guideline-based medical management alone (control group). The primary efficacy end point was the mean score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes, according to patients’ assessment) at 180 days, with a prespecified threshold for posterior probability of superiority of 0.975 or higher. The trial included rules for adaptation of enrollment criteria on the basis of hemorrhage location. A primary safety end point was death within 30 days after enrollment.
结果
共计300例患者被纳入试验，其中30.7%患前基底神经节出血，69.3%患脑叶出血。纳入175例患者后，本试验启动调整规则，只纳入脑叶出血患者。180天时，手术组的效用加权改良Rankin量表平均评分为0.458，对照组为0.374（差异，0.084；95%贝叶斯可信区间，0.005~0.163；手术组具有优效性的后验概率，0.981）。在脑叶出血患者中，组间平均差异为0.127（95%贝叶斯可信区间，0.035~0.219），而在前基底神经节出血患者中，组间平均差异为－0.013（95%贝叶斯可信区间，－0.147~0.116）。手术组的30天内死亡率为9.3%，对照组为18.0%。手术组5例患者（3.3%）出现术后再出血和神经功能恶化。
Result
A total of 300 patients were enrolled, of whom 30.7% had anterior basal ganglia hemorrhages and 69.3% had lobar hemorrhages. After 175 patients had been enrolled, an adaptation rule was triggered, and only persons with lobar hemorrhages were enrolled. The mean score on the utility-weighted modified Rankin scale at 180 days was 0.458 in the surgery group and 0.374 in the control group (difference, 0.084; 95% Bayesian credible interval, 0.005 to 0.163; posterior probability of superiority of surgery, 0.981). The mean between-group difference was 0.127 (95% Bayesian credible interval, 0.035 to 0.219) among patients with lobar hemorrhages and −0.013 (95% Bayesian credible interval, −0.147 to 0.116) among those with anterior basal ganglia hemorrhages. The percentage of patients who had died by 30 days was 9.3% in the surgery group and 18.0% in the control group. Five patients (3.3%) in the surgery group had postoperative rebleeding and neurologic deterioration.
结论
对于可在急性脑出血后24小时内接受手术的患者，180天时，接受血肿微创清除术患者的功能结局优于单纯接受基于指南的药物治疗的患者。手术效果似乎归功于对脑叶出血的干预。（由Nico资助；ENRICH在ClinicalTrials.gov注册号为NCT02880878）。
ConclusionsAmong patients in whom surgery could be performed within 24 hours after an acute intracerebral hemorrhage, minimally invasive hematoma evacuation resulted in better functional outcomes at 180 days than those with guideline-based medical management. The effect of surgery appeared to be attributable to intervention for lobar hemorrhages. (Funded by Nico; ENRICH ClinicalTrials.gov number, NCT02880878.)
Gustavo Pradilla, Jonathan J. Ratcliff, Alex J. Hall, et al. Trial of Early Minimally Invasive Removal of Intracerebral Hemorrhage. DOI:10.1056/NEJMoa23084403
脑室内输注CARv3-TEAM-E T细胞治疗复发性胶质母细胞瘤试验
Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma
摘 要
摘要
在此项由研究者发起，首次应用于人体的开放标签研究中，3例复发性胶质母细胞瘤患者接受了CARv3-TEAM-E T细胞治疗，CARv3-TEAM-E T细胞是经过基因工程改造，靶向表皮生长因子受体（EGFR）变异型III肿瘤特异性抗原，并且通过分泌T细胞结合抗体分子（TEAM）靶向野生型EGFR蛋白的嵌合抗原受体（CAR）T细胞。CARv3-TEAM-E T细胞治疗未产生超过3级的不良事件或剂量限制性毒性。肿瘤的影像学消退显著而迅速，发生在接受一次脑室内输注后数天内，但3例患者中有2例的缓解持续时间短暂。（由Gateway for Cancer Research等资助；INCIPIENT在ClinicalTrials.gov注册号为NCT05660369）。
BackgroundAbstractIn this first-in-human, investigator-initiated, open-label study, three participants with recurrent glioblastoma were treated with CARv3-TEAM-E T cells, which are chimeric antigen receptor (CAR) T cells engineered to target the epidermal growth factor receptor (EGFR) variant III tumor-specific antigen, as well as the wild-type EGFR protein, through secretion of a T-cell–engaging antibody molecule (TEAM). Treatment with CARv3-TEAM-E T cells did not result in adverse events greater than grade 3 or dose-limiting toxic effects. Radiographic tumor regression was dramatic and rapid, occurring within days after receipt of a single intraventricular infusion, but the responses were transient in two of the three participants. (Funded by Gateway for Cancer Research and others; INCIPIENT ClinicalTrials.gov number, NCT05660369.)
Bryan D. Choi, Elizabeth R. Gerstner, Matthew J. Frigault, et al. Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma. DOI:10.1056/NEJMoa2314390
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