Purpose: Dynamic changes in circulating tumor DNA (ctDNA) are under investigation as an early indicator of treatment outcome. Experimental Design: Serial plasma ctDNA (baseline, 8 weeks, and at progression) was prospectively incorporated into the SWOG S1403 clinical trial of afatinib ± cetuximab in tyrosine kinase inhibitor—naïve, EGFR mutation tissue–positive non–small cell lung cancer. Results: EGFR mutations were detected in baseline ctDNA in 77% (82/106) of patients, associated with the presence of brain and/or liver metastases and M1B stage. Complete clearance of EGFR mutations in ctDNA by 8 weeks was associated with a significantly decreased risk of progression, compared with those with persistent ctDNA at Cycle 3 Day 1 [HR, 0.23; 95% confidence interval (CI), 0.12–0.45; P < 0.0001], with a median progression-free survival (PFS) of 15.1 (95% CI, 10.6–17.5) months in the group with clearance of ctDNA versus 4.6 (1.7–7.5) months in the group with persistent ctDNA. Clearance was also associated with a decreased risk of death (HR, 0.44; 95% CI, 0.21–0.90), P = 0.02; median overall survival (OS): 32.6 (23.5–not estimable) versus 15.6 (4.9–28.3) months. Conclusions: Plasma clearance of mutant EGFR ctDNA at 8 weeks was highly and significantly predictive of PFS and OS, outperforming RECIST response for predicting long-term benefit.

中文翻译：

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循环肿瘤 DNA 动力学预测 EGFR TKI 治疗的 EGFR 突变 NSCLC 患者的无进展生存期和总体生存期 (SWOG S1403)


目的：正在研究循环肿瘤 DNA (ctDNA) 的动态变化，作为治疗结果的早期指标。实验设计：连续血浆 ctDNA（基线、8 周和进展时）前瞻性地纳入阿法替尼 ± 西妥昔单抗治疗酪氨酸激酶抑制剂（首次使用、EGFR 突变组织阳性非小细胞肺癌）的 SWOG S1403 临床试验中。结果：77% (82/106) 的患者在基线 ctDNA 中检测到 EGFR 突变，与脑和/或肝转移以及 M1B 分期的存在相关。与第 3 个周期第 1 天持续存在 ctDNA 的患者相比，8 周内 ctDNA 中 EGFR 突变的完全清除与进展风险显着降低相关[HR，0.23； 95% 置信区间 (CI)，0.12–0.45； P < 0.0001]，ctDNA 清除组的中位无进展生存期 (PFS) 为 15.1 (95% CI，10.6–17.5) 个月，而 ctDNA 持续存在组为 4.6 (1.7–7.5) 个月。清除还与死亡风险降低相关（HR，0.44；95% CI，0.21-0.90），P = 0.02；中位总生存期 (OS)：32.6（23.5-不可估计）与 15.6（4.9-28.3）个月。结论：8 周时突变 EGFR ctDNA 的血浆清除率高度且显着地预测 PFS 和 OS，在预测长期获益方面优于 RECIST 反应。