SCI

28 July 2024

Impact of EML4-ALK variants and co-occurring TP53 mutations on duration of first-line ALK tyrosine kinase inhibitor treatment and overall survival in ALK fusion-positive NSCLC: Real-world outcomes from the GuardantINFORM database

（Journal of Thoracic Oncology；IF：21）

  • Parikh K, Dimou A, Leventakos K, Mansfield AS, Shanshal M, Wan Y, Lin HM, Vincent S, Elliott J, Bonta IR. Impact of EML4-ALK variants and co-occurring TP53 mutations on duration of first-line ALK tyrosine kinase inhibitor treatment and overall survival in ALK fusion-positive NSCLC: Real-world outcomes from the GuardantINFORM database. J Thorac Oncol. 2024 Jul 15:S1556-0864(24)00677-4. doi: 10.1016/j.jtho.2024.07.009. Epub ahead of print. PMID: 39019326.

  • Corresponding Author: Kaushal Parikh, Assistant Professor of Oncology, Mayo Clinic Comprehensive Cancer Center, 200 First Street SW, Rochester, MN, 55905, USA,Phone: 507-293-0569 ,E-mail: Parikh.Kaushal@mayo.edu

Introduction 引言

Tyrosine kinase inhibitors (TKIs) are first-line treatment options for ALK-positive (ALK+) non-small cell lung cancer (NSCLC). Factors such as variant allele frequencies (VAF), EML4-ALK fusion variant, and concurrent TP53 mutations (TP53mt) in circulating tumor DNA (ctDNA) may affect treatment outcomes. We evaluated their effects on time to discontinuation (TTD) of first-line treatment with next-generation ALK TKIs in a real-world setting.

酪氨酸激酶抑制剂（TKIs）是ALK阳性（ALK+）非小细胞肺癌（NSCLC）的一线治疗选择。循环肿瘤DNA（ctDNA）中的变异等位基因频率（VAF）、EML4-ALK融合变异和伴随的TP53突变（TP53mt）等因素可能会影响治疗结果。我们在真实世界环境中评估了这些因素对下一代ALK TKIs一线治疗中治疗中止时间（TTD）的影响。

 

Methods 方法

Adults with advanced/metastatic NSCLC and ctDNA-detected ALK fusion who received first-line next-generation ALK TKI monotherapy were identified in GuardantINFORM. Effects of ALK fusion VAF, EML4-ALK variants, and TP53mt detection on TTD were evaluated.

在GuardantINFORM数据库中，确定了接受一线下一代ALK TKI单药治疗且ctDNA检测到ALK融合的晚期/转移性NSCLC成人患者。评估了ALK融合VAF、EML4-ALK变异和TP53mt检测对TTD的影响。

 

Results 结果

307 patients with ALK fusion in baseline ctDNA received first-line alectinib (n=280), brigatinib (n=15), lorlatinib (n=9), or ceritinib (n=3); 150 patients (49%) had ALK-fusion VAF ≥1%. Among 232 patients with EML4-ALK fusions (v1, 50%; v3, 36%), TP53mt co-occurred with v1 in 42 (18%) and v3 in 32 (14%). Patients with VAF <1% versus ≥1% had median TTD of 32.2 (95% CI: 20.7-NE) versus 14.7 months (10.4-19.9; HR: 1.57 [95% CI: 1.09-2.26]; P=0.0146). Median TTD was 13.1 (9.5-19.9) versus 27.6 months (17.3-not estimable [NE]) in patients with versus without TP53mt detected (HR: 1.53 [1.07-2.19]; P=0.0202) and 20.3 (14.4-NE) versus 11.5 months (7.4-31.1) in patients with v1 versus v3 (HR: 1.29 [0.83-2.01]; P=0.2641). Patients with TP53mt and v3 had median TTD of 7.4 months (95% CI: 4.2-31.1).

在基线ctDNA中检测到ALK融合的307名患者接受了一线治疗，包括阿来替尼（n=280）、布加替尼（n=15）、劳拉替尼（n=9）或色瑞替尼（n=3）；其中150名患者（49%）的ALK融合VAF≥1%。在232名具有EML4-ALK融合（v1，50%；v3，36%）的患者中，TP53mt与v1共现于42例（18%），与v3共现于32例（14%）。VAF <1%的患者与VAF≥1%的患者的中位TTD分别为32.2个月（95% CI：20.7-NE）和14.7个月（10.4-19.9；HR：1.57 [95% CI：1.09-2.26]；P=0.0146）。在检测到TP53mt的患者中，中位TTD为13.1个月（9.5-19.9），而在未检测到TP53mt的患者中，中位TTD为27.6个月（17.3-未估计[NE]）（HR：1.53 [1.07-2.19]；P=0.0202）。具有v1的患者与具有v3的患者的中位TTD分别为20.3个月（14.4-NE）和11.5个月（7.4-31.1）（HR：1.29 [0.83-2.01]；P=0.2641）。具有TP53mt和v3的患者的中位TTD为7.4个月（95% CI：4.2-31.1）。

 

Conclusion 结论

High ctDNA VAF, EML4-ALK v3, and TP53mt were associated with early discontinuation of first-line ALK TKIs.

高水平的ctDNA VAF、EML4-ALK v3和TP53mt与早期中止使用一线ALK TKI正相关。