信迪利单抗联合化疗治疗EGFR-TKI治疗后病情进展的EGFR突变型非小细胞肺癌患者（ORIENT-31）：第二次中期分析

SCI 9 May 2023

Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial

(The Lancet Respiratory Medicine, IF: 102.642)

Shun Lu, Lin Wu, Hong Jian, Ying Cheng, Qiming Wang, Jian Fang, Ziping Wang, Yanping Hu, Liang Han, Meili Sun, Liyun Miao, Cuimin Ding, Jiuwei Cui, Ke Wang, Baolan Li, Xingya Li, Feng Ye, Anwen Liu, Yueyin Pan, Shundong Cang, Hui Zhou, Xing Sun, Yuping Shen, Shuyan Wang, Wen Zhang, Yue He

CORRESPONDENCE TO: shunlu@sjtu.edu.cn

Background 背景  

In the first interim analysis of the ORIENT-31 trial, compared with chemotherapy alone, sintilimab plus bevacizumab biosimilar IBI305 plus chemotherapy (pemetrexed and cisplatin) significantly improved progression-free survival in patients with EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC) who progressed on EGFR tyrosine-kinase inhibitor treatment. However, the benefit of anti-PD-1 or PD-L1 antibody added to chemotherapy in this patient population remains unclear, with no prospective evidence from phase 3 trials globally. We report the results from the prespecified second interim analysis of progression-free survival between sintilimab plus chemotherapy and chemotherapy alone, the updated results of sintilimab plus IBI305 plus chemotherapy, and preliminary overall survival results.

在ORIENT-31试验的第一次中期分析中，与单独化疗相比，在应用了EGFR酪氨酸激酶抑制剂治疗疾病进展的EGFR突变的非小细胞肺癌（NSCLC）患者中，信迪利单抗加贝伐单抗生物类似物药IBI305加化疗（培美曲塞和顺铂）显著提高了他们的无进展生存率。然而，抗PD-1或PD-L1抗体药物联合化疗在该患者群体中的益处尚不清楚，全球3期试验没有前瞻性证据。我们报告了预先指定的第二次中期分析的结果，即信迪利单抗联合化疗和单独化疗之间的无进展生存率，信迪利单抗联合IBI305联合化疗的最新结果，以及初步的总生存率结果。

Methods 方法  

This double-blind, randomised, placebo-controlled, phase 3 trial was done at 52 centres across China and included patients aged 18–75 years with locally advanced or metastatic (stage IIIB, IIIC, or IV according to the American Joint Committee on Cancer, eighth edition) EGFR-mutated non-squamous NSCLC, disease progression after EGFR tyrosine-kinase inhibitor treatment (according to the Response Evaluation Criteria in Solid Tumours version 1.1 [RECIST 1.1]), and at least one measurable lesion (according to RECIST 1.1). Patients were randomly assigned (1:1:1), using an interactive web response system, to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m²) and cisplatin (75 mg/m²), sintilimab plus chemotherapy, or chemotherapy alone on day 1 of each 3-week cycle for four cycles, followed by maintenance therapy of sintilimab, IBI305, and pemetrexed. All study drugs were administered intravenously. The primary endpoint was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee. Data cutoff was March 31, 2022, unless otherwise specified. The study is registered at ClinicalTrials.gov, NCT03802240 (ongoing).

这项双盲、随机、安慰剂对照的3期临床试验在中国52个中心进行，纳入了年龄在18-75岁的局部晚期或转移性（根据美国癌症联合委员会第八版分期IIIB、IIIC或IV期）EGFR-突变非鳞状非小细胞肺癌患者，并且在EGFR酪氨酸激酶抑制剂治疗后的疾病发生进展（根据实体瘤反应评估标准1.1版[RECIST 1.1]）和至少一个可测量的病变（根据RECIST 1.1）。患者被随机分配（1:1:1），使用交互式网络反应系统，在每个3周周期的第1天接受信迪利单抗（200 mg）加IBI305（15 mg/kg）加培美曲塞（500 mg/m²）和顺铂（75 mg/m²），或信迪利单抗加化疗，或单独化疗，总计持续4周期。所有研究药物均通过静脉注射给药。主要终点是由独立的放射学审查委员会评估的意向治疗人群的无进展生存率。数据截止日期为2022年3月31日，除非另有规定。该研究已在ClinicalTrials.gov，NCT03802240上注册（正在进行中）。

Findings 结果  

Between July 11, 2019, and March 31, 2022, 1011 patients were screened and 476 were randomly assigned (158 to the sintilimab plus IBI305 plus chemotherapy group, 158 to the sintilimab plus chemotherapy group, and 160 to the chemotherapy alone group). The median follow-up duration for progression-free survival was 12∙9 months (IQR 8∙2–17∙8) in the sintilimab plus IBI305 plus chemotherapy group, 15∙1 months (8∙0–19∙5) in the sintilimab plus chemotherapy group, and 14∙4 months (9∙8–23∙8) in the chemotherapy alone group. Sintilimab plus chemotherapy significantly improved progression-free survival compared with chemotherapy alone (median 5∙5 months [95% CI 4∙5–6∙1] vs 4∙3 months [4∙1–5∙3]; hazard ratio [HR] 0∙72 [95% CI 0∙55–0∙94]; two-sided p=0∙016). Significant progression-free survival benefit was sustained with sintilimab plus IBI305 plus chemotherapy compared with chemotherapy alone (median 7∙2 months [95% CI 6·6–9·3]; HR: 0∙51 [0∙39–0∙67]; two-sided p<0∙0001). As of data cutoff (July 4, 2022), the median overall survival was 21·1 months (95% CI 17·5–23·9) for sintilimab plus IBI305 plus chemotherapy (HR 0·98 [0·72–1·34]) and 20·5 months (15·8–25·3) for sintilimab plus chemotherapy group (HR 0·97 [0·71–1·32]) versus 19·2 months (15·8–22·4) for chemotherapy alone; after adjusting for crossover, the HR for sintilimab plus IBI305 plus chemotherapy to chemotherapy alone ranged from 0·79 (0·57–1·09) to 0·84 (0·61–1·15) and the HR for sintilimab plus chemotherapy to chemotherapy alone ranged from 0·78 (0·57–1·08) to 0·84 (0·61–1·16). The safety results were generally consistent with those in the first interim analysis; in particular, treatment-related adverse events of grade 3 or worse occurred in 88 (56%) of 158 patients in the sintilimab plus IBI305 plus chemotherapy group, 64 (41%) of 156 patients in the sintilimab plus chemotherapy group, and 79 (49%) of 160 patients in the chemotherapy alone group.

在2019年7月11日至2022年3月31日期间，对1011名患者进行了筛查，476名患者被随机分配（158名患者被分配到信迪利单抗加IBI305加化疗组，158名患者分配到信迪利单抗加化疗组和160名患者被分到单独化疗组）。信迪利单抗加IBI305加化疗组无进展生存期的中位随访时间为12∙9个月（IQR 8∙2–17∙8），信迪利单抗加化疗组为15∙1个月（8∙0–19∙5），单独化疗组为14∙4个月（9∙8–23∙8。与单独化疗相比，信迪利单抗联合化疗显著提高了无进展生存率（中位5个月[95%CI 4∙5-6∙1]vs 4∙3个月[4∙1-5∙3]；危险比[HR]0∙72[95%CI 0∙55–0∙94]；双侧p=0∙016）。与单独化疗相比，信迪利单抗加IBI305加化疗可获得持续显著的无进展生存获益（中位7∙2个月[95%CI 6/6-9.3]；HR:0∙51[0∙39-0∙67]；双侧p<0∙0001）。截至数据截止日期（2022年7月4日），信迪利单抗加IBI305加化疗组的中位总生存期为21.1个月（95%CI 17.5–23.9）（HR 0.98[0.72–1.34]），信迪利单抗加化疗组的中位总生存期为20.5个月（15.8–25.3）（HR 0.77[0.71–1.32]），而单独化疗组的中位总生存期为19.2个月（12.8–22.4）；在调整交叉后，信迪利单抗加IBI305加化疗与单独化疗的HR范围为0.79（0.57-1.09）至0.84（0.61-1.15），信迪利单抗加化疗与单纯化疗的HR为0.78（0.57-1.08）至0.804（0.61-1 16）。安全性结果与第一次中期分析中的结果基本一致；特别是，信迪利单抗加IBI305加化疗组158名患者中有88人（56%）、信迪利单抗加化疗组156名患者中64人（41%）和单独化疗组160名患者中79人（49%）发生了3级或更严重的治疗相关不良事件。

Interpretation 解释  

This is the first prospective phase 3 trial to show the benefit of anti-PD-1 antibody plus chemotherapy in patients with EGFR-mutated NSCLC who progressed on treatment with tyrosine-kinase inhibitors. Compared with chemotherapy alone, sintilimab combined with pemetrexed and cisplatin showed significant and clinically meaningful improvement of progression-free survival with an optimal safety profile. Sintilimab plus IBI305 plus chemotherapy continued to show progression-free survival benefit compared with chemotherapy alone in this second interim analysis with an additional 8-month follow-up.

这是第一项显示抗PD-1抗体加化疗对EGFR突变的NSCLC患者在应用酪氨酸激酶抑制剂治疗后疾病发生了进展的益处的前瞻性3期试验。与单独化疗相比，信迪利单抗联合培美曲塞和顺铂在无进展生存率方面表现出显著和临床意义的改善，具有最佳的安全性。在第二次中期分析中，与单独化疗相比，信迪利单抗加IBI305加化疗继续显示出无进展生存益处，并进行了额外的8个月随访。

Funding 资金来源  

National Natural Science Foundation of China, Shanghai Municipal Science & Technology Commission Research Project, and Innovent Biologics.

国家自然科学基金、上海市科委研究项目、创新生物。

打赏