van 't Erve Iris, Blanchard Isabelle, Pagtama Judy Y, Holmes Tisch Alison J, Alizadeh Ash A, Ramchandran Kavitha, Wakelee Heather A, Padda Sukhmani K, Diehn Maximilian, Neal Joel W
Stanford Cancer Institute, Stanford University, Stanford, California.
Department of Radiation Oncology, Stanford University, Stanford, California.
JTO Clin Res Rep. 2025 Jul 10;6(9):100877. doi: 10.1016/j.jtocrr.2025.100877. eCollection 2025 Sep.
Immune checkpoint inhibitors provide clinical benefit to a subset of patients with metastatic NSCLC, yet the reliable prediction of long-term outcomes remains challenging. We conducted a prospective phase 2 clinical trial to evaluate circulating tumor DNA (ctDNA) as a surrogate biomarker for early clinical response to pembrolizumab monotherapy (NCT02955758). Tumor-informed targeted sequencing of pretreatment and early on-treatment plasma ctDNA in 25 patients with metastatic NSCLC was performed. On-treatment ctDNA response, defined as at least a threefold ctDNA variant allele frequency decrease after three cycles of pembrolizumab versus baseline, was able to predict with 100%, 66%, and 100% accuracy partial response, stable disease, and progressive disease radiologic response, respectively. Molecular response was also correlated with progression-free survival. This study confirms the potential clinical utility of early on-treatment ctDNA-based response evaluation in patients treated with immune checkpoint inhibitors, creating the opportunity for early treatment intervention in nonresponders.
免疫检查点抑制剂可为一部分转移性非小细胞肺癌（NSCLC）患者带来临床益处，但对长期疗效进行可靠预测仍具有挑战性。我们开展了一项前瞻性2期临床试验，以评估循环肿瘤DNA（ctDNA）作为帕博利珠单抗单药治疗早期临床反应替代生物标志物的价值（NCT02955758）。对25例转移性NSCLC患者治疗前及治疗早期血浆ctDNA进行肿瘤知情靶向测序。治疗期ctDNA反应定义为帕博利珠单抗三个周期治疗后ctDNA变异等位基因频率较基线至少降低三倍，该反应分别能够以100%、66%和100%的准确率预测部分缓解、疾病稳定和疾病进展的放射学反应。分子反应也与无进展生存期相关。本研究证实了基于治疗期早期ctDNA的反应评估在接受免疫检查点抑制剂治疗患者中的潜在临床应用价值，为无反应者进行早期治疗干预创造了机会。
