Department of Radiation Oncology, Stanford University, Stanford, California; Stanford Cancer Institute, Stanford University, Stanford, California.
Community Hospital Oncology Physicians, Community Health Network MD Anderson Comprehensive Cancer Center, Indianapolis, Indiana.
J Thorac Oncol. 2024 Oct;19(10):1427-1437. doi: 10.1016/j.jtho.2024.06.024. Epub 2024 Jul 5.
The current standard of care for patients with inoperable stage III non-small cell lung cancer includes chemoradiotherapy (CRT) followed by 1 year of checkpoint inhibitor (CPI) therapy. Nevertheless, the optimal duration of consolidation CPI remains unknown. Here, we characterized the relationship between circulating tumor DNA (ctDNA) minimal residual disease (MRD) and clinical outcomes of patients with unresectable locally advanced non-small cell lung cancer treated on a phase 2 trial of short-course consolidation immunotherapy after CRT, with the goal of testing whether ctDNA may be able to identify patients who do not require a full year of treatment.
Plasma samples for ctDNA analysis were collected from patients on the Big Ten Cancer Research Consortium LUN 16-081 trial after completion of CRT, before day 1 of cycle 2 (C2D1) of CPI (i.e., 1 mo after treatment start), and at the end of up to 6 months of treatment. Tumor-informed ctDNA MRD analysis was performed using cancer personalized profiling by deep sequencing. Levels of ctDNA at each time point were correlated with clinical outcomes.
Detection of ctDNA predicted significantly inferior progression-free survival after completion of CRT (24-mo 29% versus 65%, p = 0.0048), before C2D1 of CPI (24-mo 0% versus 72%, p < 0.0001) and at the end of CPI (24-mo 15% versus 67%, p = 0.0011). In addition, patients with decreasing or undetectable ctDNA levels after 1 cycle of CPI had improved outcomes compared with patients with increasing ctDNA levels (24-mo progression-free survival 72% versus 0%, p < 0.0001). Progression of disease occurred within less than 12 months of starting CPI in all patients with increasing ctDNA levels at C2D1.
Detection of ctDNA before, during, or after 6 months of consolidation CPI is strongly associated with inferior outcomes. Our findings suggest that analysis of ctDNA MRD may enable personalizing the duration of consolidation immunotherapy treatment.
对于无法手术的 III 期非小细胞肺癌患者，目前的治疗标准包括放化疗（CRT）后接受 1 年的检查点抑制剂（CPI）治疗。然而，巩固性 CPI 的最佳持续时间仍不清楚。在这里，我们描述了无法切除的局部晚期非小细胞肺癌患者在 CRT 后接受短期巩固性免疫治疗的 2 期试验中，循环肿瘤 DNA（ctDNA）微小残留疾病（MRD）与临床结果之间的关系，目的是测试 ctDNA 是否能够识别不需要进行全年治疗的患者。
在 CRT 完成后、CPI 第 2 周期（C2D1）前（即治疗开始后 1 个月）和最多 6 个月的治疗结束时，从 Big Ten Cancer Research Consortium LUN 16-081 试验的患者中采集血浆样本进行 ctDNA 分析。使用深度测序的癌症个体化分析进行基于肿瘤的 ctDNA MRD 分析。在每个时间点检测 ctDNA 与临床结果相关。
CRT 完成后检测到 ctDNA 预测无进展生存期明显较差（24 个月 29%对 65%，p=0.0048），CPI 的 C2D1 前（24 个月 0%对 72%，p<0.0001）和 CPI 结束时（24 个月 15%对 67%，p=0.0011）。此外，与 ctDNA 水平升高的患者相比，1 周期 CPI 后 ctDNA 水平降低或无法检测的患者有更好的结局（24 个月无进展生存期 72%对 0%，p<0.0001）。在所有 C2D1 时 ctDNA 水平升高的患者中，疾病进展发生在开始 CPI 后不到 12 个月内。
在巩固性 CPI 前、期间或后检测到 ctDNA 与预后不良密切相关。我们的研究结果表明，ctDNA MRD 分析可能使巩固性免疫治疗的持续时间个体化。
