劳拉替尼治疗晚期ALK阳性非小细胞肺癌患者的早期ctDNA动力学和疗效

端午安康

SCI

22 June 2023

Early ctDNA dynamics and efficacy of lorlatinib in patients with treatment-naive, advanced, ALK-positive non-small cell lung cancer

(Journal of Thoracic Oncology, IF: 20.121)

Ross A. Soo, Jean-François Martini, Anthonie J. van der Wekken, Shunsuke Teraoka, Roberto Ferrara, Alice T. Shaw, Deborah Shepard, Anna Maria Calella, Anna Polli, Francesca Toffalorio, Pascale Tomasini, Chao-Hua Chiu, Dariusz Kowalski, Hye Ryun Kim, Benjamin J. Solomon

CORRESPONDENCE TO: ross_soo@nuhs.edu.sg

Introduction 介绍  

Circulating tumor DNA (ctDNA) has been used as a biomarker for prognostication and response to treatment. Here, we evaluate ctDNA as a potential biomarker for response to lorlatinib, a third generation ALK tyrosine kinase inhibitor in patients with treatment-naive, advanced, ALK-positive non small cell lung cancer (NSCLC) in the ongoing phase 3 CROWN study (NCT03052608).

循环肿瘤DNA（ctDNA）已被用作预测和评估治疗反应的生物标志物。在这里，我们评估ctDNA作为一种潜在的生物标记物，用于反映在正在进行的3期CROWN研究（NCT03052608）中接受第三代ALK酪氨酸激酶抑制剂劳拉替尼治疗的晚期ALK阳性初次治疗的非小细胞肺癌（NSCLC）患者的反应。

Methods 方法  

Molecular responses were calculated using mean variant allele frequency (VAF), longitudinal mean change in VAF (dVAF), and ratio to baseline. Efficacy assessments (progression-free survival [PFS] and objective response rate) were paired with individual patient ctDNA and analyzed for association.

使用平均变异等位基因频率（VAF）、VAF的纵向平均变化（dVAF）和与基线的比率来计算分子反应。疗效评估（无进展生存期[PFS]和客观有效率）与个体患者ctDNA配对，并分析其相关性。

Results 结果  

Compared to baseline, mean VAF at week 4 was decreased in both treatment arms. Considering all detected somatic variants, a reduction in dVAF (≤0) was associated with a longer PFS in the lorlatinib arm. The hazard ratio (HR) for dVAF ≤0 vs >0 was 0.50 (95% CI, 0.23-1.12) in the lorlatinib arm. A similar association was not observed for crizotinib (HR, 1.00; 95% CI, 0.49-2.03). Comparing molecular responders vs nonresponders, patients treated with lorlatinib who had a molecular response had longer PFS (HR, 0.37; 95% CI, 0.16-0.85); patients treated with crizotinib who had a molecular response had similar PFS as those without a molecular response (HR, 1.48; 95% CI, 0.67-3.30).

与基线相比，两个治疗组在第4周的平均VAF均降低。考虑到所有检测到的体细胞变异，劳拉替尼组的dVAF（≤0）降低与PFS延长有关。劳拉替尼组dVAF≤0 与 dVAF>0的危险比（HR）为0.50（95%CI，0.23-1.12）。克唑替尼没有观察到类似的相关性（HR，1.00；95%置信区间，0.49-2.03）。比较分子应答者与无应答者，接受劳拉替尼治疗的有分子应答的患者PFS更长（HR，0.37；95%可信区间，0.16-0.85）；有分子应答的克唑替尼治疗的患者与没有分子应答的患者具有相似的PFS（HR，1.48；95%CI，0.67-3.30）。

Conclusion 结论  

In patients with treatment-naive, advanced, ALK-positive NSCLC, early ctDNA dynamics predicted better outcome with lorlatinib, but not with crizotinib. These results suggest ctDNA may be used to monitor and potentially predict efficacy of lorlatinib treatment.

在针对未曾接受过治疗的晚期ALK阳性的非小细胞肺癌患者的治疗中，早期ctDNA动力学预测劳拉替尼的疗效更好，但克唑替尼没有相应疗效。这些结果表明ctDNA可用于监测和潜在预测劳拉替尼治疗的疗效。

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