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桓兴医讯 Durvalmab作为晚期非小细胞肺癌的三线或更晚治疗方案(
文章来源:北京市朝阳区桓兴肿瘤医院 点击数: 发布时间:2019-08-19 14:29
柳叶刀2018年3月12日
Durvalmab作为晚期非小细胞肺癌的三线或更晚治疗方案(ATLANTIC试验):一项开放标签的单臂2期研究
背景
对于EGFR酪氨酸激酶或间变性淋巴瘤激酶(ALK)基因无变异(EGFR-/ALK-)的晚期非小细胞肺癌(NSCLC)患者,免疫检查点抑制剂是一种新的标准治疗,但在EGFR突变或ALK重排(EGFR+/ALK+)的患者中未显示临床获益。因此,我们根据EGFR/ALK状态和PD-L1肿瘤表达情况,将非小细胞肺癌患者分为3个队列,在这3个队列中,我们评估了durvalumab(抗PD-L1)的疗效。
方法
ATLANTIC是一项2期、开放标签、单臂试验,在亚洲、欧洲和北美的139家研究中心实施。符合条件的患者为
1.晚期非小细胞肺癌
2.至少两次既往全身治疗后进展,既往全身治疗包括含铂化疗(和符合适应症的酪氨酸激酶抑制剂治疗)
3.年满18岁
4.世卫组织的体能状况评分为0或1分
5.按照实体瘤疗效评估标准(RECIST)1.1版,有可测量病灶。
主要排除标准包括混合型小细胞肺癌+非小细胞肺癌组织成分、既往抗PD-1或抗PD-L1抗体治疗过、以前接受任何免疫治疗药物时出现过≥3级免疫相关不良事件。队列1的患者为EGFR+/ALK+的非小细胞肺癌,PD-L1表达的肿瘤细胞≥25%,或<25%;队列2和3的非小细胞肺癌患者均为EGFR-/ALK-,队列2纳入了PD-L1表达的肿瘤细胞≥25%或<25%的患者,队列3纳入的患者为PD-L1表达的肿瘤细胞≥90%。(尽管是一篇长长的摘要,但此处每个队列下的亚组分层[PD-L1表达的肿瘤细胞≥25%或<25%],文章摘要未交代,容易迷惑读者——译者注)。通过静脉输注,患者每2周接受一次durvalumab(10mg/kg),长达12个月。对于完成12个月治疗后获益,但后来进展的患者,允许再次治疗。主要终点是PD-L1肿瘤高表达(即队列1和队列2中定义为≥25%,队列3中≥90%)患者获得客观缓解的比例,根据实体瘤疗效评价标准(RECIST)1.1版,由独立评估中心在可评估的患者中对缓解情况进行评估。在所有接受了至少一剂durvalumab且有用药后数据的患者中评估安全性。该试验仍在进行中,但不再开放招募,该试验已在ClinicalTrials.gov网站注册,编号NCT02087423。
发现
2014年2月25日至2015年12月28日,444名患者入组并接受durvalumab治疗:队列1为111名,队列2为265名,队列3为68名。在肿瘤细胞表达PD-L1至少25%的患者中,由独立评估中心对客观缓解情况进行评估,队列1,74名患者中有9名(12.2%,95%CI,5.7-21.8)获得了客观缓解,队列2,146名患者中有24名(16.4%,95%CI,10.8-23.5)获得了客观缓解,队列3,68名患者中有21名(30.9%,95%CI,20.2-43.3)获得了客观缓解。总体上,444名患者中有40名(9%)发生了3、4级治疗相关不良事件:队列1中111名患者中6名(5%),队列2中265名中22名(8%),队列3中68名中12名(18%)。最常见的治疗相关的3、4级不良事件是肺炎(4名患者[1%])、γ-谷氨酰转移酶升高(4名[1%])、腹泻(3名[1%])、输注相关反应(3名[1%])、天门冬氨酸转氨酶升高(2名[<1%])、转氨酶升高(2名[<1%])、呕吐(2名[<1%])和疲劳(2名[<1%])。总体上,444名患者中27名(6%)发生了治疗相关的严重不良事件:队列1中111名患者有5名(5%)、队列2中265名有14名(5%)、队列3中68名有8名(12%)。总体上,最常见的严重不良事件为肺炎(5名[1%])、疲劳(3名[1%])和输注相关反应(3名[1%])。免疫介导的事件采用标准治疗指南可控。
解释
在晚期、既往密集治疗过的非小细胞肺癌患者中,durvalumab的临床活性和安全性与其他抗PD-1、抗PD-L1药物一致。所有队列中均记录到有缓解,EGFR-/ALK-非小细胞肺癌(队列2和3)获得缓解的患者比例高于EGFR+/ALK+非小细胞肺癌(队列1)。在EGFR+非小细胞肺癌、且表达PD-L1的肿瘤细胞≥25%的患者中,durvalumab的临床活性令人鼓舞,需要在EGFR+/ALK+非小细胞肺癌患者中对durvalumab进一步研究。
北京市朝阳区桓兴肿瘤医院 桓兴医讯编译组 吴永勇
2019年8月19日 星期一
Published: 12 March 2018
DOI: https://doi.org/10.1016/S1470-2045(18)30144-X
Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study
Background
Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR−/ALK−), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1.
Methods
ATLANTIC is a phase 2, open-label, single-arm trial at 139 study centres in Asia, Europe, and North America. Eligible patients had advanced NSCLC with disease progression following at least two previous systemic regimens, including platinum-based chemotherapy (and tyrosine kinase inhibitor therapy if indicated); were aged 18 years or older; had a WHO performance status score of 0 or 1; and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key exclusion criteria included mixed small-cell lung cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1 antibody; and any previous grade 3 or worse immune-related adverse event while receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC with at least 25%, or less than 25%, of tumour cells with PD-L1 expression. Patients in cohorts 2 and 3 had EGFR−/ALK− NSCLC; cohort 2 included patients with at least 25%, or less than 25%, of tumour cells with PD-L1 expression, and cohort 3 included patients with at least 90% of tumour cells with PD-L1 expression. Patients received durvalumab (10 mg/kg) every 2 weeks, via intravenous infusion, for up to 12 months. Retreatment was allowed for patients who benefited but then progressed after completing 12 months. The primary endpoint was the proportion of patients with increased tumour expression of PD-L1 (defined as ≥25% of tumour cells in cohorts 1 and 2, and ≥90% of tumour cells in cohort 3) who achieved an objective response, assessed in patients who were evaluable for response per independent central review according to RECIST version 1.1. Safety was assessed in all patients who received at least one dose of durvalumab and for whom any post-dose data were available. The trial is ongoing, but is no longer open to accrual, and is registered with ClinicalTrials.gov, number NCT02087423.
Findings
Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and received durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among patients with at least 25% of tumour cells expressing PD-L1 who were evaluable for objective response per independent central review, an objective response was achieved in 9 (12·2%, 95% CI 5·7–21·8) of 74 patients in cohort 1 and 24 (16·4%, 10·8–23·5) of 146 patients in cohort 2. In cohort 3, 21 (30·9%, 20·2–43·3) of 68 patients achieved an objective response. Grade 3 or 4 treatment-related adverse events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most common treatment-related grade 3 or 4 adverse events were pneumonitis (four patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three [1%]), infusion-related reaction (three [1%]), elevated aspartate aminotransferase (two [<1%]), elevated transaminases (two [<1%]), vomiting (two [<1%]), and fatigue (two [<1%]). Treatment-related serious adverse events occurred in 27 (6%) of 444 patients overall: five (5%) of 111 patients in cohort 1, 14 (5%) of 265 in cohort 2, and eight (12%) of 68 in cohort 3. The most common serious adverse events overall were pneumonitis (five patients [1%]), fatigue (three [1%]), and infusion-related reaction (three [1%]). Immune-mediated events were manageable with standard treatment guidelines.
Interpretation
In patients with advanced and heavily pretreated NSCLC, the clinical activity and safety profile of durvalumab was consistent with that of other anti-PD-1 and anti-PD-L1 agents. Responses were recorded in all cohorts; the proportion of patients with EGFR–/ALK– NSCLC (cohorts 2 and 3) achieving a response was higher than the proportion with EGFR+/ALK+ NSCLC (cohort 1) achieving a response. The clinical activity of durvalumab in patients with EGFR+ NSCLC with ≥25% of tumour cells expressing PD-L1 was encouraging, and further investigation of durvalumab in patients with EGFR+/ALK+ NSCLC is warranted.

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