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期刊来源：JAMA

原文链接：https://doi.org/10.1001/jama.2024.10613

摘要内容如下：

重要性

对于在接受EGFR酪氨酸激酶抑制剂（EGFR-TKI）治疗（特别是第三代TKI）期间疾病进展的非小细胞肺癌患者，最佳治疗选择仍然有限。

目的

比较ivonescimab联合化疗与单纯化疗对表皮生长因子受体（EGFR）变异的复发性晚期或转移性非小细胞肺癌患者的疗效。

设计、设置和参与者

在中国55个地点开展的双盲、安慰剂对照、随机、3期试验于2022年1月至2022年11月招募了参与者；共招募了322名符合条件的患者。

干预措施

受试者接受ivonescimab（n=161）或安慰剂（n=161）联合培美曲塞和卡铂，每3周一次，共4个周期，然后接受ivonescimab联合培美曲塞或安慰剂联合培美曲塞的维持治疗。

主要成果和措施

主要终点是意向治疗人群的无进展生存期，由独立的放射学审查委员会（IRRC）根据实体瘤疗效评价标准1.1版进行评估。报告了第一次计划中期分析的结果。

结果

在ivonescimab组和安慰剂组的322名入选患者中，中位年龄分别为59.6岁和59.4岁，女性患者分别占52.2%和50.9%。截至2023年3月10日，中位随访时间为7.89个月。ivonescimab组的中位无进展生存期为7.1（95%CI，5.9-8.7）个月，安慰剂组为4.8（95%CI，4.2-5.6）个月（差异，2.3个月；风险比[HR]，0.46[95%CI，0.34-0.62]；P<.001）。预先指定的亚组分析显示，在几乎所有亚组中，接受ivonescimab治疗的患者的无进展生存获益均优于安慰剂，包括接受第三代EGFR-TKI治疗时疾病进展的患者（HR，0.48[95%CI，0.35-0.66]）和脑转移患者（HR，0.40[95%CI，0.22-0.73]）。IVonescimab组的客观有效率为50.6%（95%CI，42.6%-58.6%），安慰剂组为35.4%（95%CI，28.0%-43.3%）（差异，15.6%[95%CI，5.3%-26.0%]；P=.006）。中位总生存数据不成熟；数据截止时，69名患者（21.4%）死亡。3级或更高级别的治疗中出现的不良事件在ivonescimab组中有99例（61.5%），而在安慰剂组中有79例（49.1%），其中最常见的是化疗相关的不良事件。ivonescimab组有10名患者（6.2%）发生3级或更高级别的免疫相关不良事件，而安慰剂组有4名患者（2.5%）。3级或更高的血管内皮生长因子相关不良事件在ivonescimab组中有5例（3.1%），而在安慰剂组中有4例（2.5%）。

结论

ivonescimab联合化疗显著改善了TKI治疗的非小细胞肺癌患者的无进展生存期，且安全性可耐受。

试用注册

ClinicalTrials.gov标识符：NCT05184712。

英文原文如下：

Abstracts

Importance  For patients with non-small cell lung cancer whose disease progressed while receiving EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy, particularly third-generation TKIs, optimal treatment options remain limited.

Objective  To compare the efficacy of ivonescimab plus chemotherapy with chemotherapy alone for patients with relapsed advanced or metastatic non-small cell lung cancer with the epidermal growth factor receptor (EGFR) variant.

Design, Setting, and Participants  Double-blind, placebo-controlled, randomized, phase 3 trial at 55 sites in China enrolled participants from January 2022 to November 2022; a total of 322 eligible patients were enrolled.

Interventions  Participants received ivonescimab (n = 161) or placebo (n = 161) plus pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy of ivonescimab plus pemetrexed or placebo plus pemetrexed.

Main Outcomes and Measures  The primary end point was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee (IRRC) per Response Evaluation Criteria in Solid Tumors version 1.1. The results of the first planned interim analysis are reported.

Results  Among 322 enrolled patients in the ivonescimab and placebo groups, the median age was 59.6 vs 59.4 years and 52.2% vs 50.9% of patients were female. As of March 10, 2023, median follow-up time was 7.89 months. Median progression-free survival was 7.1 (95% CI, 5.9-8.7) months in the ivonescimab group vs 4.8 (95% CI, 4.2-5.6) months for placebo (difference, 2.3 months; hazard ratio [HR], 0.46 [95% CI, 0.34-0.62]; P < .001). The prespecified subgroup analysis showed progression-free survival benefit favoring patients receiving ivonescimab over placebo across almost all subgroups, including patients whose disease progressed while receiving third-generation EGFR-TKI therapy (HR, 0.48 [95% CI 0.35-0.66]) and those with brain metastases (HR, 0.40 [95% CI, 0.22-0.73]). The objective response rate was 50.6% (95% CI, 42.6%-58.6%) with ivonescimab and 35.4% (95% CI, 28.0%-43.3%) with placebo (difference, 15.6% [95% CI, 5.3%-26.0%]; P = .006). The median overall survival data were not mature; at data cutoff, 69 patients (21.4%) had died. Grade 3 or higher treatment-emergent adverse events occurred in 99 patients (61.5%) in the ivonescimab group vs 79 patients (49.1%) in the placebo group, the most common of which were chemotherapy-related. Grade 3 or higher immune-related adverse events occurred in 10 patients (6.2%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Grade 3 or higher vascular endothelial growth factor-related adverse events occurred in 5 patients (3.1%) in the ivonescimab group vs 4 (2.5%) in the placebo group.

Conclusions  Ivonescimab plus chemotherapy significantly improved progression-free survival with tolerable safety profile in TKI-treated non-small cell lung cancer.

Trial Registration  ClinicalTrials.gov Identifier: NCT05184712.

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