Circulating tumor DNA dynamic variation predicts sotorasib efficacy in KRASp.G12C-mutated advanced non-small cell lung cancer

IF 6.1 2区医学 Q1 ONCOLOGY

Cancer Pub Date : 2025-05-30 DOI:10.1002/cncr.35917

Francesco Passiglia MD, PhD, Francesco Pepe PhD, Gianluca Russo PhD, Edoardo Garbo MD, Angela Listì PhD, Federica Benso PhD, Claudia Scimone PhD, Lucia Palumbo PhD, Monica Pluchino PhD, Roberta Minari PhD, Paola Bordi MD, Massimiliano Cani MD, Antonio Ungaro MD, Chiara Ambrogio PhD, Riccardo Taulli MD, PhD, Enrica Capelletto MD. PhD, Maurizio Balbi MD, PhD, Luisella Righi MD, PhD, Marcello Tiseo MD, PhD, Diana Giannarelli PhD, Giancarlo Troncone MD, PhD, Silvia Novello MD, PhD, Umberto Malapelle PhD

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引用次数: 0

Abstract

Background

The objective of this study was to investigate the correlation between circulating tumor DNA (ctDNA) KRAS G12C–mutation dynamic variations and treatment outcomes in patients with advanced non-small cell lung cancer (NSCLC) receiving sotorasib therapy in a real-world setting.

Methods

Peripheral blood samples were prospectively collected from 32 patients at baseline, at cycle 3, and then at each radiologic assessment during sotorasib treatment. Both tissue and plasma samples were analyzed by using ultra-deep, customized next-generation sequencing (NGS) assays. Plasma samples from 27 of 32 patients also were analyzed by digital polymerase chain reaction analysis, and ctDNA dynamic variations were correlated with radiologic responses and patients' clinical outcomes.

Results

A significant correlation between NGS and digital polymerase chain reaction–detected KRAS G12C variant allelic fractions (p < .001) was observed. Patients who achieved clearance of KRAS G12C–mutant ctDNA levels had a significant improvement in the objective response rate (80% vs. 8%; p < .001), median progression-free survival (7.9 vs. 2.8 months; p < .001), and median overall survival (16.8 vs. 6.4 months; p < .001) compared with those who did not achieve clearance. The clearance of ctDNA was the only prognostic factor significantly associated with both median progression-free survival (hazard ratio, 0.15; 95% confidence interval, 0.04–0.48) and median overall survival (hazard ratio, 0.09; 95% confidence interval, 0.02–0.45) in multivariable analysis. Moreover, a dynamic increase in the KRAS G12C median variant allele fraction anticipated radiologic disease progression in 70% of patients who were evaluable at the resistance time point.

Conclusions

This study demonstrated that early clearance of KRAS G12C–mutant ctDNA predicted the clinical benefit of sotorasib in patients with advanced NSCLC, suggesting that dynamic monitoring of ctDNA levels also may anticipate sotorasib resistance.

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循环肿瘤DNA动态变化预测sotorasib在KRASp中的疗效。g12c突变的晚期非小细胞肺癌

本研究的目的是探讨在现实环境中接受sotorasib治疗的晚期非小细胞肺癌（NSCLC）患者循环肿瘤DNA (ctDNA) KRAS g12c突变动态变化与治疗结果的相关性。方法前瞻性地收集32例患者的外周血样本，分别在基线、第3周期和索托拉西布治疗期间的每次放射学评估时进行。组织和血浆样品均采用超深定制的下一代测序（NGS）分析。对32例患者中27例的血浆样本进行了数字聚合酶链反应分析，ctDNA动态变化与放射学反应和患者临床结果相关。结果NGS与数字聚合酶链反应检测的KRAS G12C变异等位基因片段有显著相关性(p <；.001)。清除KRAS g12c -突变ctDNA水平的患者在客观缓解率方面有显著改善(80% vs. 8%；p & lt;.001)，中位无进展生存期(7.9 vs 2.8个月；p & lt;.001)，中位总生存期(16.8 vs 6.4个月；p & lt;.001)。ctDNA清除率是唯一与中位无进展生存期显著相关的预后因素(风险比，0.15；95%可信区间，0.04-0.48)和中位总生存期(风险比，0.09；95%置信区间为0.02-0.45)。此外，KRAS G12C中位变异等位基因分数的动态增加预示着70%在耐药时间点可评估的患者的放射学疾病进展。本研究表明，KRAS g12c突变体ctDNA的早期清除可以预测sotorasib在晚期NSCLC患者中的临床获益，提示动态监测ctDNA水平也可以预测sotorasib耐药性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer 医学-肿瘤学

CiteScore

13.10

自引率

3.20%

发文量

480

审稿时长

2-3 weeks

期刊介绍： The CANCER site is a full-text, electronic implementation of CANCER, an Interdisciplinary International Journal of the American Cancer Society, and CANCER CYTOPATHOLOGY, a Journal of the American Cancer Society. CANCER publishes interdisciplinary oncologic information according to, but not limited to, the following disease sites and disciplines: blood/bone marrow; breast disease; endocrine disorders; epidemiology; gastrointestinal tract; genitourinary disease; gynecologic oncology; head and neck disease; hepatobiliary tract; integrated medicine; lung disease; medical oncology; neuro-oncology; pathology radiation oncology; translational research