Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial
Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial
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DOI：
10.1016/s2213-2600(19)30084-0
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发表时间：
2019-05-01
影响因子：
76.2
通讯作者：
Socinski, Mark A.
中科院分区：
文献类型：
--
作者：
Reck, Martin;Mok, Tony S. K.;Socinski, Mark A.
IMpower 150试验显示，atezolizumab+贝伐单抗+卡铂+紫杉醇（ABCP）与标准治疗的贝伐单抗+卡铂+紫杉醇（BCP）相比，在未经化疗的非鳞状非小细胞肺癌患者中，无进展生存期和总生存期显著改善。在这里，我们报告ABCP或atezolizumab加卡铂加紫杉醇（ACP）与BCP的疗效在关键patient subgroup.Methods IMpower 150是一个随机的，开放标签，3期研究在240个学术医疗中心和社区肿瘤学实践在全球26个国家。未经化疗的转移性非小细胞肺癌患者被随机分配（1：1：1）接受ABCP，ACP或BCP，每三周一次。共同主要终点是意向治疗野生型患者的总生存期和经评估的无进展生存期（排除了表皮生长因子受体[EGFR]或间变性淋巴瘤激酶[ALK]基因改变的患者）。在意向治疗人群的关键亚组中评估疗效，包括既往接受过一种或多种酪氨酸激酶抑制剂治疗的EGFR突变（致敏和非致敏; EGFR阳性）患者和基线肝转移患者。意向治疗人群的总生存期被纳入次要疗效终点。探索性终点包括意向治疗人群中达到客观缓解的患者比例，包括EGFR阳性患者和基线肝转移患者。根据数据截止日期2018年1月22日报告数据，在该日期，ABCP组与BCP组符合共同主要预先规定的总生存期事件数量。本试验已在ClinicalTrials注册。在2015年3月31日至2016年12月30日期间，招募了1202名患者。400例患者随机分配至ABCP组，402例患者分配至ACP组，400例患者分配至BCP组。EGFR阳性患者（124/1202）中，ABCP组（34/400）的中位总生存期不可估计（NE; 95% CI 17.0-NE），BCP组（45/400;风险比[HR] 0.61 [95% CI 0.29-1.28]）为18.7个月（95% CI 13.4-NE）。在有致敏EGFR突变的患者中观察到ABCP相比BCP的总生存期改善（ABCP组中位总生存期NE [95% CI NE-NE][26/400] vs BCP组中位总生存期17.5个月[95% CI 11.7-NE][32/400]; HR 0.31 [95% CI 0.11-0.83]）和意向治疗人群（19.8个月[17.4-24.2] vs 14.9个月[13.4-17.1]; HR 0.76 [0.63-0.93]）。在基线肝转移患者中观察到ABCP与BCP相比的中位总生存期延长（ABCP组13.3个月[11.6-NE][52/400] vs BCP组9.4个月[7.9-11.7][57/400]; HR 0.52 [0.33-0.82]）。在EGFR阳性患者中，ACP组的中位总生存期为21.4个月（95% CI 13.8-NE），BCP组为18.7个月（95% CI 13.4-NE）（HR 0.93 [95% CI 0.51-1.68]）。在致敏EGFR突变患者（HR 0.90 [95% CI 0.47-1.74]）、意向治疗人群（HR 0.85 [0.71-1.03]）或基线肝转移患者（HR 0.87 [0.57-1.32]）中，ACP与BCP相比未观察到总生存期获益。在意向治疗安全性可评价人群中，ABCP组223例（57%）患者、ACP组172例（43%）患者和BCP组191例（49%）患者发生3-4级治疗相关事件; ABCP组发生11例（3%）5级不良事件，ACP组发生4例（1%），BCP组9例（2%）。解释：在意向治疗人群中，与BCP组相比，ABCP组患者的生存率提高，和基线肝转移患者。EGFR致敏突变患者亚组的总生存信号需要进一步研究。版权所有（c）2019 Elsevier Ltd.保留所有权利。
Background The IMpower150 trial showed significant improvements in progression-free and overall survival with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) versus the standard-of-care bevacizumab plus carboplatin plus paclitaxel (BCP) in chemotherapy-naive patients with non-squamous non-small-cell lung cancer. Here, we report the efficacy of ABCP or atezolizumab plus carboplatin plus paclitaxel (ACP) versus BCP in key patient subgroups.Methods IMpower150 was a randomised, open-label, phase 3 study done at 240 academic medical centres and community oncology practices across 26 countries worldwide. Patients with chemotherapy-naive metastatic nonsmall-cell lung cancer were randomly assigned (1: 1: 1) to receive ABCP, ACP, or BCP every three weeks. The co-primary endpoints were overall survival and investigator-assessed progression-free survival in intention-to-treat wild-type patients (patients with epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] genetic alterations were excluded). Efficacy was assessed in key subgroups within the intention-to-treat population, including patients with EGFR mutations (both sensitising and non-sensitising; EGFR-positive) previously treated with one or more tyrosine kinase inhibitors and patients with baseline liver metastases. Overall survival in the intention-to-treat population was included among secondary efficacy endpoints. Exploratory endpoints included the proportion of patients achieving an objective response in the intention-to-treat population, including EGFR-positive patients and patients with baseline liver metastases. Data are reported as per the Jan 22, 2018, data cutoff date, at which the number of coprimary prespecified overall survival events was met in the ABCP versus BCP groups. This trial is registered with ClinicalTrials. gov, number NCT02366143, and is ongoing.Findings Between March 31, 2015, and Dec 30, 2016, 1202 patients were enrolled. 400 patients were randomly assigned to ABCP, 402 to ACP, and 400 to BCP. In EGFR-positive patients (124 of 1202), median overall survival was not estimable (NE; 95% CI 17.0-NE) with ABCP (34 of 400) and 18.7 months (95% CI 13.4-NE) with BCP (45 of 400; hazard ratio [HR] 0.61 [95% CI 0.29-1.28]). Improved overall survival with ABCP versus BCP was observed in patients with sensitising EGFR mutations (median overall survival NE [95% CI NE-NE] with ABCP [26 of 400] vs 17.5 months [95% CI 11.7-NE] with BCP [32 of 400]; HR 0.31 [95% CI 0.11-0.83]) and in the intention-to-treat population (19.8 months [17.4-24.2] vs 14.9 months [13.4-17.1]; HR 0.76 [0.63-0.93]). Improved median overall survival with ABCP versus BCP was seen in patients with baseline liver metastases (13.3 months [11.6-NE] with ABCP [52 of 400] vs 9.4 months [7.9-11.7] with BCP [57 of 400]; HR 0.52 [0.33-0.82]). Median overall survival was 21.4 months (95% CI 13.8-NE) with ACP versus 18.7 months (95% CI 13.4-NE) with BCP in EGFR-positive patients (HR 0.93 [95% CI 0.51-1.68]). No overall survival benefit was seen with ACP versus BCP in patients with sensitising EGFR mutations (HR 0.90 [95% CI 0.47-1.74]), in the intention-to-treat population (HR 0.85 [0.71-1.03]), or in patients with baseline liver metastases (HR 0.87 [0.57-1.32]). In the intention-to-treat safety-evaluable population, grade 3-4 treatment-related events occurred in 223 (57%) patients in the ABCP group, in 172 (43%) in the ACP group, and in 191 (49%) in the BCP group; 11 (3%) grade 5 adverse events occurred in the ABCP group, as did four (1%) in the ACP group, and nine (2%) in the BCP group.Interpretation Improved survival was noted for patients treated with ABCP compared with those given BCP in the intention-to-treat population, and in patients with baseline liver metastases. The overall survival signal in the subgroup of patients with EGFR sensitising mutations warrants further study. Copyright (c) 2019 Elsevier Ltd. All rights reserved.