治疗晚期或复发性子宫内膜癌的阿替珠单抗和化疗(AtTEnd):随机、双盲、安慰剂对照的 3 期试验。

IF 41.6 1区 医学 Q1 ONCOLOGY
Lancet Oncology Pub Date : 2024-09-01 Epub Date: 2024-08-02 DOI:10.1016/S1470-2045(24)00334-6
Nicoletta Colombo, Elena Biagioli, Kenichi Harano, Francesca Galli, Emma Hudson, Yoland Antill, Chel Hun Choi, Manuela Rabaglio, Frederic Marmé, Christian Marth, Gabriella Parma, Lorena Fariñas-Madrid, Shin Nishio, Karen Allan, Yeh Chen Lee, Elisa Piovano, Beatriz Pardo, Satoshi Nakagawa, John McQueen, Claudio Zamagni, Luis Manso, Kazuhiro Takehara, Giulia Tasca, Annamaria Ferrero, Germana Tognon, Andrea Alberto Lissoni, Mariacristina Petrella, Maria Elena Laudani, Eliana Rulli, Sara Uggeri, M Pilar Barretina Ginesta
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引用次数: 0

摘要

背景:在设计AtTEnd试验时,晚期或复发性子宫内膜癌的标准治疗包括卡铂和紫杉醇化疗。该试验评估了将阿特珠单抗与化疗相结合是否能改善这一人群的治疗效果:AtTEnd是一项多中心、双盲、随机、安慰剂对照的3期试验,在欧洲、澳大利亚、新西兰和亚洲11个国家的89家医院进行。入组患者年龄在18岁或以上,患有晚期或复发性子宫内膜癌或癌肉瘤,东部合作肿瘤学组表现为0-2级,既往未因复发接受过系统化疗。患者通过交互式网络响应系统(每组6人)被随机分配(2:1)至阿替佐珠单抗1200毫克或安慰剂,同时静脉注射化疗药物(卡铂曲线下面积为5或6,紫杉醇175毫克/平方米,静脉注射,每21天1天),共6-8个周期,然后继续治疗直至病情恶化。分层因素包括国家、组织学亚型、晚期或复发状态以及错配修复(MMR)状态。参与者和主治临床医生均被蒙蔽,不知道分组情况。分层测试的共同主要终点是无进展生存期(MMR缺陷[dMMR]肿瘤患者和总体人群)和总生存期(总体人群)。主要分析是在意向治疗人群中进行的,意向治疗人群是指所有随机分配并完全同意参与研究和数据处理的患者。对所有纳入意向治疗人群并至少接受过一次治疗的患者进行了安全性评估。我们在此报告主要无进展生存期和中期总生存期结果。这项研究正在进行中,已在ClinicalTrials.gov上注册,编号为NCT03603184.研究结果:2018年10月3日至2022年1月7日期间,551名患者被随机分配到atezolizumab(n=362)或安慰剂(n=189)。atezolizumab组的两名患者因未获得同意而被排除在所有分析之外。中位随访时间为 28-3 个月(IQR 21-2-37-6)。经中心评估,阿特珠单抗组中有 81 例(23%)患者患有 dMMR 疾病,安慰剂组中有 44 例(23%)患者患有 dMMR 疾病。在dMMR人群中,atezolizumab组的中位无进展生存期无法估计(95% CI 12-4个月-无法估计[NE]),安慰剂组为6-9个月(6-3-10-1)(危险比[HR]0-36,95% CI 0-23-0-57;P=0-0005)。在总体人群中,atezolizumab组的中位无进展生存期为10-1个月(95% CI 9-5-12-3),安慰剂组为8-9个月(8-1-9-6)(HR 0-74,95% CI 0-61-0-91;P=0-022)。阿特珠单抗组的中位总生存期为38-7个月(95% CI 30-6-NE),安慰剂组为30-2个月(25-0-37-2)(HR 0-82,95% CI 0-63-1-07;对数秩p=0-048)。总生存期中期分析的 p 值未超过停止界限;因此,试验将继续进行,直至记录到所需的事件数。最常见的3-4级不良事件是中性粒细胞减少症(阿替佐珠单抗组356名患者中有97人[27%],安慰剂组185名患者中有51人[28%])和贫血(49人[14%],安慰剂组24人[13%])。atezolizumab组有46名患者(13%)发生了与治疗相关的严重不良事件,安慰剂组有6名患者(3%)发生了与治疗相关的严重不良事件。有两名患者发生了与治疗相关的死亡(两组各有一名患者死于肺炎):atezolizumab联合化疗提高了晚期或复发性子宫内膜癌患者的无进展生存期,尤其是在dMMR癌患者中,这表明在标准化疗的基础上,atezolizumab可作为这一特殊亚组的一线治疗药物:F Hoffmann-La Roche.
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Atezolizumab and chemotherapy for advanced or recurrent endometrial cancer (AtTEnd): a randomised, double-blind, placebo-controlled, phase 3 trial.

Background: At the time of AtTEnd trial design, standard treatment for advanced or recurrent endometrial cancer included carboplatin and paclitaxel chemotherapy. This trial assessed whether combining atezolizumab with chemotherapy might improve outcomes in this population.

Methods: AtTEnd was a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done in 89 hospitals in 11 countries across Europe, Australia, New Zealand, and Asia. Enrolled patients were aged 18 years or older, and had advanced or recurrent endometrial carcinoma or carcinosarcoma, an Eastern Cooperative Oncology Group performance status of 0-2, and received no previous systemic chemotherapy for recurrence. Patients were randomly assigned (2:1) using an interactive web response system (block size of six) to either atezolizumab 1200 mg or placebo given intravenously with chemotherapy (carboplatin at area under the curve of 5 or 6 and paclitaxel 175 mg/m2 intravenously on day 1 every 21 days) for 6-8 cycles, then continued until progression. Stratification factors were country, histological subtype, advanced or recurrent status, and mismatch repair (MMR) status. Participants and treating clinicians were masked to group allocation. The hierarchically tested co-primary endpoints were progression-free survival (in patients with MMR-deficient [dMMR] tumours, and in the overall population) and overall survival (in the overall population). Primary analyses were done in the intention-to-treat population, defined as all randomly assigned patients who gave their full consent to participation in the study and data processing. Safety was assessed in all patients included in the intention-to-treat population who received at least one dose of study treatment. Here, we report the primary progression-free survival and the interim overall survival results. This study is ongoing and is registered with ClinicalTrials.gov, NCT03603184.

Findings: Between Oct 3, 2018, and Jan 7, 2022, 551 patients were randomly assigned to atezolizumab (n=362) or placebo (n=189). Two patients in the atezolizumab group were excluded from all analyses due to lack of consent. Median follow-up was 28·3 months (IQR 21·2-37·6). 81 (23%) patients in the atezolizumab group and 44 (23%) patients in the placebo group had dMMR disease by central assessment. In the dMMR population, median progression-free survival was not estimable (95% CI 12·4 months-not estimable [NE]) in the atezolizumab group and 6·9 months (6·3-10·1) in the placebo group (hazard ratio [HR] 0·36, 95% CI 0·23-0·57; p=0·0005). In the overall population, median progression-free survival was 10·1 months (95% CI 9·5-12·3) in the atezolizumab group and 8·9 months (8·1-9·6) in the placebo group (HR 0·74, 95% CI 0·61-0·91; p=0·022). Median overall survival was 38·7 months (95% CI 30·6-NE) in the atezolizumab group and 30·2 months (25·0-37·2) in the placebo group (HR 0·82, 95% CI 0·63-1·07; log-rank p=0·048). The p value for the interim analysis of overall survival did not cross the stopping boundary; therefore, the trial will continue until the required number of events are recorded. The most common grade 3-4 adverse events were neutropenia (97 [27%] of 356 patients in the atezolizumab group vs 51 [28%] of 185 in the placebo group) and anaemia (49 [14%] vs 24 [13%]). Treatment-related serious adverse events occurred in 46 (13%) patients in the atezolizumab group and six (3%) patients in the placebo group. Treatment-related deaths occurred in two patients (pneumonia in one patient in each group).

Interpretation: Atezolizumab plus chemotherapy increased progression-free survival in patients with advanced or recurrent endometrial carcinoma, particularly in those with dMMR carcinomas, suggesting the addition of atezolizumab to standard chemotherapy as first-line treatment in this specific subgroup.

Funding: F Hoffmann-La Roche.

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来源期刊
Lancet Oncology
Lancet Oncology 医学-肿瘤学
CiteScore
62.10
自引率
1.00%
发文量
913
审稿时长
3-8 weeks
期刊介绍: The Lancet Oncology is a trusted international journal that addresses various topics in clinical practice, health policy, and global oncology. It covers a wide range of cancer types, including breast, endocrine system, gastrointestinal, genitourinary, gynaecological, haematological, head and neck, neurooncology, paediatric, thoracic, sarcoma, and skin cancers. Additionally, it includes articles on epidemiology, cancer prevention and control, supportive care, imaging, and health-care systems. The journal has an Impact Factor of 51.1, making it the leading clinical oncology research journal worldwide. It publishes different types of articles, such as Articles, Reviews, Policy Reviews, Personal Views, Clinical Pictures, Comments, Correspondence, News, and Perspectives. The Lancet Oncology also collaborates with societies, governments, NGOs, and academic centers to publish Series and Commissions that aim to drive positive changes in clinical practice and health policy in areas of global oncology that require attention.
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