Department of Oncology, Mayo Clinic, Rochester, Minnesota.
Department of Oncology, Mayo Clinic, Rochester, Minnesota.
J Thorac Oncol. 2024 Nov;19(11):1539-1549. doi: 10.1016/j.jtho.2024.07.009. Epub 2024 Jul 15.
Tyrosine kinase inhibitors (TKIs) are first-line treatment options for ALK-positive (ALK+) NSCLC. Factors such as variant allele frequencies (VAFs), 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.
Adults with advanced or 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.
A total of 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 greater than or equal to 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 less than 1% versus greater than or equal to 1% had a median TTD of 32.2 (95% confidence interval [CI]: 20.7-not estimable [NE]) versus 14.7 months (10.4-19.9; hazard ratio [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-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 a median TTD of 7.4 months (95% CI: 4.2-31.1).
High ctDNA VAF, EML4-ALK v3, and TP53mt were associated with early discontinuation of first-line ALK TKIs.
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 融合变体和同时存在的 TP53 突变（TP53mt）等因素可能会影响治疗结果。我们在真实环境中评估了它们对一线治疗中下一代 ALK TKI 停药时间（TTD）的影响。
在 GuardantINFORM 中，鉴定了基线 ctDNA 中检测到 ALK 融合并接受一线下一代 ALK TKI 单药治疗的晚期或转移性 NSCLC 成人患者。评估了 ALK 融合 VAF、EML4-ALK 变体和 TP53mt 检测对 TTD 的影响。
共有 307 名基线 ctDNA 中存在 ALK 融合的患者接受了一线阿来替尼（n=280）、布加替尼（n=15）、洛拉替尼（n=9）或塞瑞替尼（n=3）治疗；150 名患者（49%）的 ALK 融合 VAF 大于或等于 1%。在 232 名存在 EML4-ALK 融合（v1，50%；v3，36%）的患者中，TP53mt 与 v1 同时发生在 42 例（18%）和 v3 同时发生在 32 例（14%）。VAF 小于 1%与大于或等于 1%的患者的中位 TTD 分别为 32.2（95%置信区间[CI]：20.7-无法估计[NE]）和 14.7 个月（10.4-19.9；风险比[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（9.5-19.9），而在未检测到 TP53mt 的患者中为 27.6 个月（17.3-NE）（HR1.53 [1.07-2.19]；p=0.0202），在 v1 患者中为 20.3（14.4-NE），而在 v3 患者中为 11.5 个月（7.4-31.1）（HR1.29 [0.83-2.01]；p=0.2641）。TP53mt 和 v3 患者的中位 TTD 为 7.4 个月（95%CI：4.2-31.1）。
高 ctDNA VAF、EML4-ALK v3 和 TP53mt 与一线 ALK TKI 的早期停药相关。
