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科学家完成血液肿瘤突变负担作为非小细胞肺癌阿替利珠单抗生物标志物的临床试验
作者：小柯机器人 发布时间：2022/4/17 14:04:13

美国纽约大学Vamsidhar Velcheti等研究人员完成了血液肿瘤突变负担作为非小细胞肺癌阿替利珠单抗生物标志物的临床试验。相关论文于2022年4月14日在线发表在《自然—医学》杂志上。

研究人员表示，在回顾性研究中，循环肿瘤DNA（ctDNA）中的肿瘤突变负担（TMB）已经显示出预测PD-L1/PD-1抑制剂获益的前景。
 
为了前瞻性地评估血液TMB（bTMB），研究人员进行了B-F1RST（NCT02848651），这是一项开放标签的2期试验，评估bTMB作为局部晚期或转移性IIIB-IVB期非小细胞肺癌一线阿替利珠单抗治疗的预测生物标志物（n=152）。共同主要终点是研究者评估的RECIST 1.1版客观反应率（ORR）和研究者评估的高和低bTMB亚组之间的无进展生存期（PFS），预先定义的bTMB≥16（每兆字节14.5个突变）截止。次要终点包括研究者评估的PFS、总生存期（OS）和不同bTMB截止点的反应时间，以及安全性。在bTMB≥16组与bTMB<16组中，调查者评估的PFS没有统计学意义。然而，bTMB≥16与较高的ORR有关，而且ORR随着bTMB截止值的增加而改善。没有看到新的安全信号。在探索性分析中，最大体细胞等位基因频率（MSAF）<1%的患者比MSAF≥1%的患者的ORR更高。
 
然而，进一步的分析表明，这种效应是由更好的基线预后而不是由MSAF本身驱动的。在36.5个月的随访中，对OS的探索性分析发现，bTMB≥16与bTMB<16相关的OS更长。目前需要进一步研究和优化检测方法，从而开发bTMB作为免疫疗法的预测性、独立的生物标志物或与其他生物标志物一起使用。
 
附：英文原文
 
Title: Blood-based tumor mutational burden as a biomarker for atezolizumab in non-small cell lung cancer: the phase 2 B-F1RST trial

Author: Kim, Edward S., Velcheti, Vamsidhar, Mekhail, Tarek, Yun, Cindy, Shagan, Sarah M., Hu, Sylvia, Chae, Young Kwang, Leal, Ticiana A., Dowell, Jonathan E., Tsai, Michaela L., Dakhil, Christopher S. R., Stella, Philip, Jin, Yanling, Shames, David S., Schleifman, Erica, Fabrizio, David A., Phan, See, Socinski, Mark A.

Issue&Volume: 2022-04-14

Abstract: Tumor mutational burden (TMB) in circulating tumor DNA (ctDNA) has shown promise in predicting benefit from PD-L1/PD-1 inhibitors in retrospective studies. Aiming to assess blood TMB (bTMB) prospectively, we conducted B-F1RST (NCT02848651), an open-label, phase 2 trial that evaluated bTMB as a predictive biomarker for first-line atezolizumab monotherapy in locally advanced or metastatic stage IIIB–IVB non-small cell lung cancer (n=152). The co-primary endpoints were investigator-assessed objective response rate (ORR) per RECIST version 1.1 and investigator-assessed progression-free survival (PFS) between high and low bTMB subgroups at the pre-defined bTMB ≥16 (14.5 mutations per megabase) cutoff. Secondary endpoints included investigator-assessed PFS, overall survival (OS) and duration of response at various bTMB cutoffs, as well as safety. Investigator-assessed PFS in the bTMB≥16 versus bTMB<16 groups was not statistically significant. However, bTMB ≥ 16 was associated with higher ORR, and ORR improved as bTMB cutoffs increased. No new safety signals were seen. In exploratory analyses, patients with maximum somatic allele frequency (MSAF)<1% had higher ORR than patients with MSAF≥1%. However, further analysis showed that this effect was driven by better baseline prognostics rather than by MSAF itself. At 36.5-month follow-up, an exploratory analysis of OS found that bTMB ≥16 was associated with longer OS than bTMB <16. Further study and assay optimization will be required to develop bTMB as a predictive, standalone biomarker of immunotherapy or for use in conjunction with other biomarkers.

DOI: 10.1038/s41591-022-01754-x

Source: https://www.nature.com/articles/s41591-022-01754-x

期刊信息

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：30.641
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex