一线serpluliumab加化疗治疗广泛期小细胞肺癌:ASTRUM-005随机临床试验的最新结果和生物标志物分析

IF 20.1 1区 医学 Q1 ONCOLOGY
Ying Cheng, Shuang Zhang, Liang Han, Lin Wu, Jun Chen, Peiyan Zhao, Hongmei Sun, Guilan Wen, Yinghua Ji, Anastasia Zimina, Jianhua Shi, Zhijie Pan, Jinsheng Shi, Xicheng Wang, Yuansong Bai, Tamar Melkadze, Yueyin Pan, Xuhong Min, Maksym Viguro, Xingya Li, Yanqiu Zhao, Junquan Yang, Tamta Makharadze, Ekaterine Arkania, Haoyu Yu, Jing Li, Fang Yang, Xinyi Yang, Chen Ling, Qingyu Wang, Yongqiang Shan, Jun Zhu
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引用次数: 0

摘要

背景:ASTRUM-005研究先前证明,在先前未经治疗的广泛期小细胞肺癌(ES-SCLC)中,serplulimab(一种程序性死亡1抑制剂)联合化疗比单独化疗具有显着的总生存(OS)获益。在此,我们报告了延长中位随访19.8个月后的最新疗效和安全性结果,以及探索性生物标志物分析结果的第一份报告。方法:585例患者按2:1的比例随机分组,每3周静脉注射4.5 mg/kg的serplulimab (n = 389)或安慰剂(n = 196),同时服用卡铂和依托泊苷。主要终点为OS。此外,进行基因组分析以鉴定突变基因,并进行定量血清蛋白质组分析以鉴定serplulimab加化疗反应者和无反应者之间的差异表达蛋白(DEPs)。随后使用回归分析构建基于dep的蛋白质特征。疗效结果(客观缓解率[ORR]、OS和无进展生存期[PFS])与基因突变状态或DEP表达之间的关系也通过回归分析进行了检验。进一步评价血液学参数的预后价值。结果:在意向治疗人群中,serplulimab组的中位OS为15.8个月,而安慰剂组为11.1个月(风险比,0.62;95%置信区间为0.50-0.76;P < 0.001)。在serplulimab组中,我们在应答者和无应答者之间鉴定了181个dep,从中构建了15个蛋白特征。在serplulimab组中,具有较高15蛋白特征评分的患者与更长的OS和PFS相关。此外,与野生型患者相比,携带肿瘤抑制性视网膜母细胞瘤-1 (RB1)突变或Notch通路成员突变的患者表现出改善的ORR、OS或PFS。基线中性粒细胞与淋巴细胞比值(NLR)和乳酸脱氢酶(LDH)水平是ES-SCLC患者的独立预后指标。结论:在ES-SCLC患者中,一线serplulimab比安慰剂提供了持续的临床获益。RB1或Notch通路基因的15蛋白特征和突变可作为serplulimab加化疗获益的预测性生物标志物,而基线NLR和LDH是ES-SCLC的独立预后指标。试验注册:ClinicalTrials.gov, NCT04063163。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
First-line serplulimab plus chemotherapy in extensive-stage small-cell lung cancer: Updated results and biomarker analysis from the ASTRUM-005 randomized clinical trial.

Background: The ASTRUM-005 study previously demonstrated a significant overall survival (OS) benefit with serplulimab (a programmed death 1 inhibitor) plus chemotherapy versus chemotherapy alone in previously untreated extensive-stage small-cell lung cancer (ES-SCLC). Here, we report updated efficacy and safety results after an extended median follow-up of 19.8 months, along with the first report on findings from exploratory biomarker analyses.

Methods: A total of 585 patients were randomized in a 2:1 ratio to receive 4.5 mg/kg serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks, together with carboplatin and etoposide. The primary endpoint was OS. In addition, genomic profiling was performed to identify mutated genes, and quantitative serum proteome profiling was conducted to identify differentially expressed proteins (DEPs) between responders and non-responders of serplulimab plus chemotherapy. Regression analysis was subsequently used to construct a protein signature based on the DEPs. The associations between efficacy outcomes (objective response rate [ORR], OS, and progression-free survival [PFS]) and gene mutation status or DEP expression were also examined with regression analysis. Furthermore, the prognostic value of hematological parameters was evaluated.

Results: In the intent-to-treat population, the median OS was 15.8 months in the serplulimab group versus 11.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval, 0.50-0.76; P < 0.001). We identified 181 DEPs between responders and non-responders in the serplulimab group, from which a 15-protein signature was constructed. In the serplulimab group, patients with a higher 15-protein signature score were associated with significantly longer OS and PFS. Also, patients harboring tumor-suppressor retinoblastoma-1 (RB1) mutations or mutations in Notch pathway members showed improved ORR, OS, or PFS compared with their wild-type counterparts. Baseline neutrophil-to-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) level were independent prognosticators of patients with ES-SCLC.

Conclusions: First-line serplulimab provided a sustained clinical benefit over placebo in patients with ES-SCLC. A 15-protein signature and mutations in RB1 or Notch pathway genes may serve as predictive biomarkers for benefits from serplulimab plus chemotherapy, while baseline NLR and LDH were independent prognosticators for ES-SCLC.

Trial registration: ClinicalTrials.gov, NCT04063163.

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来源期刊
Cancer Communications
Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
25.50
自引率
4.30%
发文量
153
审稿时长
4 weeks
期刊介绍: Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.
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