University of Pennsylvania, Philadelphia, PA, USA.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Lung Cancer. 2022 Apr;166:270-278. doi: 10.1016/j.lungcan.2021.10.007. Epub 2021 Oct 19.
Effective therapy for non-small-cell lung cancer (NSCLC) depends on morphological and genomic classification, with comprehensive screening for guideline-recommended biomarkers critical to guide treatment. Companion diagnostics, which provide robust genotyping results, represent an important component of personalized oncology. We evaluated the clinical validity of Guardant360 CDx as a companion diagnostic for sotorasib for detection of KRAS p.G12C, an important oncogenic NSCLC driver mutation.
KRAS p.G12C was tested in NSCLC patients from CodeBreaK100 (NCT03600833) in pretreatment plasma samples using Guardant360 CDx liquid biopsy and archival tissue samples using therascreen® KRAS RGQ polymerase chain reaction (PCR) kit tissue testing. Matched tissue and plasma samples were procured from other clinical trials or commercial vendors, and results were compared. Demographics and clinical characteristics and objective response rate (ORR) were evaluated.
Of 126 CodeBreaK patients, 112 (88.9%) were tested for KRASp.G12C mutations with Guardant360 CDx. Among 189 patients in the extended analysis cohort, the positive and negative percent agreement (95% CI) for Guardant360 CDx plasma testing relative to therascreen® KRAS RGQ PCR kit tissue testing were 0.71 (0.62, 0.79) and 1.00 (0.95, 1.00), respectively; overall percent agreement (95% CI) was 0.82 (0.76, 0.87). TP53 co-mutations were the most common regardless of KRAS p.G12C status (KRAS p.G12C-positive, 53.4%; KRAS p.G12C-negative, 45.5%). STK11 was co-mutated in 26.1% of KRAS p.G12C-positive samples. The ORR was similar among patients selected by plasma and tissue testing.
Comprehensive genotyping for all therapeutic targets including KRAS p.G12C is critical for management of NSCLC. Liquid biopsy using Guardant360 CDx has clinical validity for identification of patients with KRASp.G12C-mutant NSCLC and, augmented by tissue testing methodologies as outlined on the approved product label, will identify patients for treatment with sotorasib.
非小细胞肺癌（NSCLC）的有效治疗取决于形态学和基因组分类，全面筛查指南推荐的生物标志物对于指导治疗至关重要。伴随诊断为个体化肿瘤学提供了重要组成部分，它可以提供可靠的基因分型结果。我们评估了 Guardant360 CDx 作为 sotorasib 伴随诊断检测 KRAS p.G12C 的临床有效性，KRAS p.G12C 是一种重要的 NSCLC 致癌驱动突变。
使用 Guardant360 CDx 液体活检检测 KRAS p.G12C 在 CodeBreaK100 （NCT03600833）预处理血浆样本中的 NSCLC 患者，使用 therascreen®KRAS RGQ 聚合酶链反应（PCR）试剂盒组织检测检测存档组织样本。从其他临床试验或商业供应商处采集匹配的组织和血浆样本，并进行比较。评估了人口统计学和临床特征以及客观缓解率（ORR）。
在 126 名 CodeBreaK 患者中，有 112 名（88.9%）使用 Guardant360 CDx 检测 KRASp.G12C 突变。在扩展分析队列的 189 名患者中，Guardant360 CDx 血浆检测相对于 therascreen®KRAS RGQ PCR 试剂盒组织检测的阳性和阴性百分比一致率（95%CI）分别为 0.71（0.62，0.79）和 1.00（0.95，1.00）；总体百分比一致率（95%CI）为 0.82（0.76，0.87）。无论 KRAS p.G12C 状态如何，TP53 共突变都是最常见的（KRAS p.G12C 阳性，53.4%；KRAS p.G12C 阴性，45.5%）。在 KRAS p.G12C 阳性样本中，STK11 共突变占 26.1%。通过血浆和组织检测选择的患者的 ORR 相似。
全面检测所有治疗靶点的基因分型，包括 KRAS p.G12C，对 NSCLC 的管理至关重要。使用 Guardant360 CDx 的液体活检具有鉴定 KRASp.G12C 突变型 NSCLC 患者的临床有效性，并结合批准产品标签上概述的组织检测方法，将确定可接受 sotorasib 治疗的患者。
