Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center, New York, New York.
Cancer Res Commun. 2024 Mar 14;4(3):786-795. doi: 10.1158/2767-9764.CRC-24-0065.
While tyrosine kinase inhibitors (TKI) have shown remarkable efficacy in anaplastic lymphoma kinase (ALK) fusion-positive advanced non-small cell lung cancer (NSCLC), clinical outcomes vary and acquired resistance remains a significant challenge. We conducted a retrospective study of patients with ALK-positive NSCLC who had clinico-genomic data independently collected from two academic institutions (n = 309). This was paired with a large-scale genomic cohort of patients with ALK-positive NSCLC who underwent liquid biopsies (n = 1,118). Somatic co-mutations in TP53 and loss-of-function alterations in CDKN2A/B were most commonly identified (24.1% and 22.5%, respectively in the clinical cohort), each of which was independently associated with inferior overall survival (HR: 2.58; 95% confidence interval, CI: 1.62-4.09 and HR: 1.93; 95% CI: 1.17-3.17, respectively). Tumors harboring EML4-ALK variant 3 (v3) were not associated with specific co-alterations but were more likely to develop ALK resistance mutations, particularly G1202R and I1171N (OR: 4.11; P < 0.001 and OR: 2.94; P = 0.026, respectively), and had inferior progression-free survival on first-line TKI (HR: 1.52; 95% CI: 1.03-2.25). Non-v3 tumors were associated with L1196M resistance mutation (OR: 4.63; P < 0.001). EML4-ALK v3 and somatic co-alterations in TP53 and CDKN2A/B are associated with inferior clinical outcomes. v3 status is also associated with specific patterns of clinically important ALK resistance mutations. These tumor-intrinsic features may inform rational selection and optimization of first-line and consolidative therapy.
In a large-scale, contemporary cohort of patients with advanced ALK-positive NSCLC, we evaluated molecular characteristics and their impact on acquired resistance mutations and clinical outcomes. Our findings that certain ALK variants and co-mutations are associated with differential survival and specific TKI-relevant resistance patterns highlight potential molecular underpinnings of the heterogenous response to ALK TKIs and nominate biomarkers that may inform patient selection for first-line and consolidative therapies.
尽管酪氨酸激酶抑制剂（TKI）在间变性淋巴瘤激酶（ALK）融合阳性的晚期非小细胞肺癌（NSCLC）中显示出显著的疗效，但临床结果存在差异，获得性耐药仍然是一个重大挑战。我们对来自两个学术机构的独立收集的临床基因组数据的 ALK 阳性 NSCLC 患者（n=309）进行了回顾性研究。该研究与接受液体活检的 ALK 阳性 NSCLC 患者的大型基因组队列（n=1118）进行了配对。TP53 的体细胞共突变和 CDKN2A/B 的功能丧失改变最常见（临床队列中分别为 24.1%和 22.5%），两者均与总生存期降低独立相关（HR：2.58；95%置信区间，CI：1.62-4.09 和 HR：1.93；95%CI：1.17-3.17）。携带 EML4-ALK 变体 3（v3）的肿瘤与特定的共改变无关，但更有可能发生 ALK 耐药突变，特别是 G1202R 和 I1171N（OR：4.11；P<0.001 和 OR：2.94；P=0.026），并且一线 TKI 治疗的无进展生存期较差（HR：1.52；95%CI：1.03-2.25）。非 v3 肿瘤与 L1196M 耐药突变相关（OR：4.63；P<0.001）。EML4-ALK v3 和 TP53 及 CDKN2A/B 的体细胞共改变与较差的临床结局相关。v3 状态也与特定的临床相关 ALK 耐药突变模式相关。这些肿瘤内在特征可能有助于一线和巩固治疗的合理选择和优化。
在一项大规模的当代晚期 ALK 阳性 NSCLC 患者队列中，我们评估了分子特征及其对获得性耐药突变和临床结局的影响。我们发现某些 ALK 变体和共突变与生存差异以及特定 TKI 相关耐药模式相关，这突出了对 ALK TKI 异质性反应的潜在分子基础，并确定了可能有助于一线和巩固治疗患者选择的生物标志物。
