表现出有前景的活性。然而，共同发生的遗传突变，如CDKN2/B或TP53，可能会对靶向治疗的疗效产生负面影响。从2017年12月至2022年12月，该研究队列分析了来自五个拉丁美洲癌症中心的116位转移性ALK重排NSCLC患者的下一代测序数据。将临床病理学和分子特征与具有和不具有共同体性改变的患者的临床结果和脑转移风险相关联。所有患者（n = 116）接受了第二代ALK-TKI治疗，其中87.2％选择了Alectinib。62％的病例中发生了共同变异，其中最常见的是TP53突变（27％）和CDKN2A/B缺失（18％）。CDKN2A/B的缺失与脑转移的风险增加相关，累积发生率为33.3％对比7.4％。与无共同突变的患者相比，有CDKN2A/B共同缺失的患者（n = 21）的中位PFS为[10.2 vs. 34.2个月; p <0.001 ]和OS[26.2 vs. 80.7个月; p <0.001]。在多变量分析中，共同发生的CDKN2A/B缺失与较差的PFS和OS相关，尽管存在其他体细胞共同突变、TP53突变、脑转移和ECOG PS。本研究验证了ALK重排患者中共同发生改变的预后价值更差的情况。CDKN2A/B的缺失与较差的结果和更高的脑转移风险显著相关。我们研究中的证据有助于选择适合治疗升级和更紧密脑部随访的ALK阳性肿瘤患者。版权所有2023年国际肺癌研究协会。由Elsevier公司出版。保留所有权利。

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have shown promising activity against advanced ALK-rearranged non-small cell lung cancer (NSCLC). However, co-occurring genetic alterations, such as CDKN2/B or TP53, may negatively affect the efficacy of targeted therapies.From December 2017 to December 2022, this study cohort analyzed Next-Generation Sequencing data of 116 patients with metastatic ALK-rearranged NSCLC from five Latin-American cancer centers. Clinicopathological and molecular features were associated with clinical outcomes and risk of brain metastasis in patients with and without concurrent somatic alterations.All patients (n=116) received a second-generation ALK-TKI, and alectinib was selected in 87.2% of cases. Co-alterations occurred in 62% of the cases; the most frequent were TP53 mutations (27%) and CDKN2A/B loss (18%). Loss of CDKN2A/B was associated with an increased risk of brain metastasis, with a cumulative incidence of 33.3% versus 7.4%. Compared with patients without co-alterations, patients with concurrent CDKN2A/B loss (n=21) had a shorter median PFS [10.2 vs. 34.2 months; p<0.001] and OS [26.2 vs. 80.7 months; p<0.001]. In the multivariate analysis, co-occurring CDKN2A/B loss was associated with poorer PFS and OS, despite the presence of other somatic co-alterations, TP53 mutations, brain metastasis, and ECOG PS.This study confirmed the worse prognostic value, which depicted co-occurring alterations in patients with ALK rearrangement. CDKN2A/B loss was significantly associated with worse outcomes and a higher risk of brain metastases. The evidence shown in our study may help select patients with ALK-positive tumors suitable for treatment escalation and closer brain follow-up.Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.