Chen Qin, Zhang Jingjing, Wang Xuan, Zong Wenkang, Sun Leina, Qin Jianwen, Yin Yan
Department of Respiratory and Critical Medicine, Tianjin Chest Hospital, Tianjin, China.
Department of Neurosurgery, Tianjin, China.
Front Oncol. 2023 Nov 1;13:1227980. doi: 10.3389/fonc.2023.1227980. eCollection 2023.
Anaplastic lymphoma kinase gene (ALK) rearrangement is present in only approximately 5% of non-small cell lung cancers (NSCLCs) and is scarce in LCNEC patients. The conventional first-line treatment options are chemotherapy combined with immunotherapy or chemotherapy followed by palliative radiotherapy. In this report, we present two cases of metastatic LCNEC with EML4-ALK fusion that were treated with ALK-TKI inhibitors and demonstrated a rapid therapeutic response. Both patients were nonsmoking women who declined cytotoxic chemotherapy, underwent Next-Generation Sequencing (NGS), and confirmed EML4-ALK fusion. They were treated with alectinib as first-line therapy, and the tumors showed significant shrinkage after two months, achieving a PR (defined as a more than 30% decrease in the sum of maximal dimensions). The PFS was 22 months and 32 months, respectively, until the last follow-up. A systematic review of all previously reported cases of LCNEC with ALK mutations identified only 21 cases. These cases were characterized by being female (71.4%), nonsmoking (85.7%), diagnosed at a relatively young age (median age 51.1), and stage IV (89.5%), with an overall response rate (ORR) of 90.5%. PFS and OS were significantly longer than those treated with conventional chemotherapy/immunotherapy. Based on the clinical characteristics and the effective therapeutic outcomes with ALK inhibitors in LCNEC patients with ALK fusion, we recommend routine ALK IHC (economical, affordable, and convenient, but with higher false positives) as a screening method in advanced LCNEC patients, particularly nonsmoking females or those who are not candidates for or unwilling to undergo cytotoxic chemotherapy. Further molecular profiling is necessary to confirm these potential beneficiaries. We suggest TKI inhibitors as the first-line treatment for metastatic LCNEC with ALK fusion. Additional studies on larger cohorts are required to assess the prevalence of ALK gene fusions and their sensitivity to various ALK inhibitors.
间变性淋巴瘤激酶基因（ALK）重排仅存在于约5%的非小细胞肺癌（NSCLC）中，在肺大细胞神经内分泌癌（LCNEC）患者中较为罕见。传统的一线治疗方案是化疗联合免疫治疗或化疗后进行姑息性放疗。在本报告中，我们展示了两例伴有EML4-ALK融合的转移性LCNEC病例，这些病例接受了ALK酪氨酸激酶抑制剂（ALK-TKI）治疗，并显示出快速的治疗反应。两名患者均为不吸烟女性，她们拒绝接受细胞毒性化疗，接受了二代测序（NGS），并确认存在EML4-ALK融合。她们接受阿来替尼作为一线治疗，两个月后肿瘤显著缩小，达到部分缓解（PR，定义为最大径之和减少超过30%）。直至最后一次随访，无进展生存期（PFS）分别为22个月和32个月。对所有先前报道的伴有ALK突变的LCNEC病例进行的系统评价仅发现21例。这些病例的特征为女性（71.4%）、不吸烟（85.7%）、诊断时年龄相对较轻（中位年龄51.1岁）以及IV期（89.5%），总缓解率（ORR）为90.5%。PFS和总生存期（OS）显著长于接受传统化疗/免疫治疗的患者。基于LCNEC伴有ALK融合患者的临床特征以及ALK抑制剂的有效治疗结果，我们建议将常规ALK免疫组化（经济、实惠且便捷，但假阳性率较高）作为晚期LCNEC患者，特别是不吸烟女性或不适合或不愿接受细胞毒性化疗患者的筛查方法。需要进一步进行分子分析以确认这些潜在的受益患者。我们建议将TKI抑制剂作为伴有ALK融合的转移性LCNEC的一线治疗。需要对更大的队列进行更多研究，以评估ALK基因融合及其对各种ALK抑制剂的敏感性的患病率。
