BACKGROUND The effectiveness of ALK inhibitors can be limited by the development of ALK resistance mutations. This exploratory analysis assessed the efficacy of alectinib in patients with non-small-cell lung cancer (NSCLC) and ALK point mutations using pooled data from two single-arm phase II studies. METHODS Studies NP28673 and NP28761 enrolled adults with locally advanced/metastatic ALK-positive NSCLC who had progressed on crizotinib. ALK mutation analysis was conducted on cell-free DNA (cfDNA) from 187 patients post-crizotinib/pre-alectinib, and from 49 of these patients who subsequently progressed on alectinib. RESULTS Baseline characteristics were generally balanced across patient subgroups. At baseline, 34 distinct ALK mutations were identified in 48/187 patients (25.7%). Median investigator-assessed progression-free survival was longer in patients without ALK single-nucleotide variants (n = 138) versus those with (n = 48): 10.2 months (95% confidence interval [CI], 8.1-14.3) versus 5.6 months (95% CI, 4.5-10.9), respectively. Sixteen out of 32 patients (50%) with ALK resistance mutations to crizotinib achieved an investigator-assessed response to alectinib (all partial responses); most of these ALK mutations were known to be sensitive to alectinib. Analysis of plasma samples taken post-progression on alectinib revealed that 26/49 (53%) samples harbored 16 distinct ALK mutations, with known alectinib-resistance mutations, I1171 T/N/S, G1202R, and V1180L, observed in 15/49 (31%) tumors. CONCLUSION Alectinib appears clinically active against ALK rearrangements and mutations, as well as several ALK variants that can cause resistance to crizotinib. The use of cfDNA in plasma samples may be an alternative non-invasive method for monitoring resistance mutations during therapy.

中文翻译：

---

艾乐替尼治疗局部晚期或转移性 ALK 阳性 NSCLC 前后的 ALK 突变状态：两项前瞻性试验的汇总分析

背景 ALK 抑制剂的有效性可能会受到 ALK 抗性突变的限制。这项探索性分析使用来自两项单臂 II 期研究的汇总数据评估了艾乐替尼在非小细胞肺癌 (NSCLC) 和 ALK 点突变患者中的疗效。方法 NP28673 和 NP28761 研究招募了在克唑替尼治疗后进展的局部晚期/转移性 ALK 阳性 NSCLC 成人。对 187 名克唑替尼后/艾乐替尼前患者的无细胞 DNA (cfDNA) 进行 ALK 突变分析，其中 49 名患者随后在艾乐替尼治疗后进展。结果 患者亚组的基线特征总体上是平衡的。在基线时，在 48/187 名患者 (25.7%) 中发现了 34 种不同的 ALK 突变。研究者评估的中位无进展生存期在没有 ALK 单核苷酸变异的患者（n = 138）与有（n = 48）的患者中更长：10.2 个月（95% 置信区间 [CI]，8.1-14.3）与 5.6 个月（95% CI，4.5-10.9），分别。对克唑替尼有 ALK 耐药突变的 32 名患者中有 16 名（50%）达到了研究者评估的对艾乐替尼的反应（所有部分反应）；已知大多数这些 ALK 突变对艾乐替尼敏感。对艾乐替尼进展后采集的血浆样本的分析显示，26/49 (53%) 的样本含有 16 个不同的 ALK 突变，已知艾乐替尼耐药突变，I1171 T/N/S、G1202R 和 V1180L，在 15/49 观察到(31%) 肿瘤。结论 阿来替尼似乎对 ALK 重排和突变具有临床活性，以及可能导致对克唑替尼耐药的几种 ALK 变体。在血浆样本中使用 cfDNA 可能是一种替代的非侵入性方法，用于监测治疗期间的耐药性突变。