循环肿瘤 DNA 的短期动力学预测替西利珠单抗联合多西他赛二线治疗晚期 NSCLC 的疗效：来自单臂、2 期试验的生物标志物分析。

Short-term dynamics of circulating tumor DNA predicting efficacy of sintilimab plus docetaxel in second-line treatment of advanced NSCLC: biomarker analysis from a single-arm, phase 2 trial.

机构信息

Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China.

Department of Radiation Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.

出版信息

J Immunother Cancer. 2022 Dec;10(12). doi: 10.1136/jitc-2022-004952.

OBJECTIVE

Robust biomarker predicting efficacy of immunotherapy is limited. Circulating tumor DNA (ctDNA) sought to effectively monitor therapeutic response as well as disease progression. This study aims to investigate predictive role of ctDNA short-term dynamic change (6 weeks postimmunotherapy) in a single-arm, phase 2 trial of sintilimab plus docetaxel for previously treated advanced non-small cell lung cancer (NSCLC) patients.

METHODS

A total of 33 patients with advanced NSCLC with disease progression during or after any first-line treatment were prospectively enrolled between 2019 and 2020. Patients received sintilimab (200 mg, day 1, every 3 weeks) plus docetaxel (75 mg/m, day 3, every 3 weeks) for 4-6 cycles, followed by maintenance therapy with sintilimab (200 mg, day 1, every 3 weeks) until disease progression or unacceptable toxic effects. Blood samples were prospectively collected at baseline, and after 2 cycles of treatment (6 weeks post-treatment). All samples were subjected to targeted next-generation sequencing with a panel of 448 cancer-related genes. The landscape of high-frequency genomic profile of baseline and 6th week was described. Major molecular characteristics in preselected genes of interest associated with response to second-line chemoimmunotherapy were analyzed. The curative effects and prognosis of patients were evaluated.

RESULTS

Patients with ctDNA clearance at 6th week had decreased tumor volume, while most patients with positive ctDNA at 6th-week experienced an increase in tumor volume. Positive 6th-week ctDNA was associated with significantly shorter progression-free survival (PFS) (91 vs NR days; p<0.0001) and overall survival (47 vs 467 days; p =0.0039). Clearance of clonal mutations and none new clonal formation at 6th week were associated with longer PFS (mPFS 89 vs 266 days, p =0.003). ctDNA clearance at 6th week was an independent risk factor for progression or death (HR=100 (95% CI 4.10 to 2503.00), p=0.005).

CONCLUSION

ctDNA status and ctDNA mutation clearance putatively serve as predictive biomarkers for sintilimab combined with docetaxel chemotherapy in pretreated advanced NSCLC patients.

目的

目前用于预测免疫治疗疗效的稳健生物标志物十分有限。循环肿瘤 DNA（ctDNA）被认为能够有效监测治疗反应和疾病进展。本研究旨在探讨在一项单臂、2 期替雷利珠单抗联合多西他赛治疗既往治疗后晚期非小细胞肺癌（NSCLC）患者的临床试验中，ctDNA 短期动态变化（免疫治疗后 6 周）的预测作用。

方法

2019 年至 2020 年期间，前瞻性纳入 33 例在任何一线治疗期间或之后发生疾病进展的晚期 NSCLC 患者。患者接受替雷利珠单抗（200mg，第 1 天，每 3 周 1 次）联合多西他赛（75mg/m2，第 3 天，每 3 周 1 次）治疗 4-6 个周期，随后使用替雷利珠单抗（200mg，第 1 天，每 3 周 1 次）维持治疗，直至疾病进展或出现不可接受的毒性作用。前瞻性采集基线和治疗 2 个周期（治疗后 6 周）后的血液样本。所有样本均采用 448 个与癌症相关基因的靶向二代测序进行检测。描述基线和第 6 周高频基因组图谱的特征。分析与二线化疗免疫治疗反应相关的预先选定基因中主要分子特征。评估患者的疗效和预后。

结果

第 6 周时 ctDNA 清除的患者肿瘤体积减小，而大多数第 6 周时 ctDNA 阳性的患者肿瘤体积增大。第 6 周时 ctDNA 阳性与无进展生存期（PFS）显著缩短（91 与 NR 天；p<0.0001）和总生存期（47 与 467 天；p=0.0039）显著相关。第 6 周时克隆突变清除且无新克隆形成与更长的 PFS 相关（mPFS 89 与 266 天，p=0.003）。第 6 周时 ctDNA 清除是进展或死亡的独立危险因素（HR=100（95%CI 4.10 至 2503.00），p=0.005）。