目的：观察中国人群肺大细胞神经内分泌癌（large cell neuroendocrine carcinoma， LCNEC）靶向突变分布特征及靶向治疗临床获益。方法：回顾性收集2021年1月至2023年12月上海交通大学医学院附属瑞金医院北部院区44例连续初治LCNEC患者。采用免疫组化检测其病理组织中的PD-L1表达情况，荧光定量PCR法检测11个驱动基因（ALK、ROS1、RET、NTRK1-3、MET、EGFR、BRAF、KRAS、HER2）突变情况。对所有患者的治疗及结局进行随访，中位随访期24个月。结果：44例LCNEC患者以男性为主（93.2%，41/44）；中位年龄70.5岁；就诊时Ⅲ、Ⅳ期占77.2%（34/44），淋巴结转移率68.2%，远处转移率47.7%。44例患者中11.4%（5例）存在可靶向突变，包括EGFR 19Del（1例）、ALK重排（1例）、MET ex14（1例）、KRAS G12C（2例）。79.5%（35/44）的患者LCNEC病理组织中程序性死亡受体配体1（programmed death-ligand 1， PD-L1）呈阴性，仅6.8%（3/44）呈PD-L1高表达（≥50%）。在34例晚期患者中，3例接受靶向治疗者的中位无进展生存期（progression free survival， PFS）为6.6个月，优于31例非靶向治疗者的4.8个月（P<0.05），EGFR突变和ALK重排患者的PFS分别达7个月和11个月，而MET ex14突变患者对靶向治疗反应不佳（PFS为2个月）。结论：在中国人群真实世界中，LCNEC侵袭性高，患者就诊时Ⅲ、Ⅳ期占七成以上，肿瘤组织中PD-L1低表达（阴性率79.5%），提示免疫治疗潜在获益人群有限；11.4%患者存在可靶向突变，携带EGFR突变和ALK重排者靶向治疗的疗效较好。分子分型对筛选LCNEC治疗优势人群可能具有重要指导价值。

Objective To investigate the distribution of targetable mutations and clinical benefits of targeted therapy in Chinese patients with pulmonary large cell neuroendocrine carcinoma (LCNEC). Methods Retrospective data were collected from 44 consecutive treatment-naive LCNEC patients at the North Campus of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine between January 2021 and December 2023. PD-L1 expression in pathological tissues was detected by immunohistochemistry, and mutations in 11 driver genes (ALK, ROS1, RET, NTRK1-3, MET, EGFR, BRAF, KRAS, HER2) were detected by quantitative real-time PCR. All patients were followed up for a median duration of 24 months. Results Among the 44 LCNEC patients, with a median age of 70.5 years, and males were predominant (93.2%, 41/44). Stage Ⅲ and Ⅳ disease accounted for 77.2% (34/44). The rates of lymph node metastasis and distant metastasis were 68.2% and 47.7%, respectively. Targetable mutations were identified in 11.4% (5/44) of the patients, including EGFR 19Del (1 case), ALK rearrangement (1 case), MET ex14 skipping mutation (1 case), and KRAS G12C mutation (2 cases). In the LCNEC pathological tissues, programmed death-ligand 1 (PD-L1) was negative in 79.5% (35/44) of the patients, while only 6.8% (3/44) demonstrated high PD-L1 expression (≥ 50%). Among the 34 Ⅲ-Ⅳ patients, the median progression-free survival (PFS) was 6.6 months in the three patients who received targeted therapy, which was significantly longer than the 4.8 months in the 31 patients who received non-targeted therapy (P < 0.05). The PFS reached 7 months and 11 months in patients with EGFR mutations and ALK rearrangements, respectively, whereas the patient with MET ex14 mutation responded poorly to targeted therapy, with a PFS of 2 months. Conclusions In the real-world Chinese population, LCNEC is highly aggressive, with over 70% of patients presenting at stage Ⅲ or Ⅳ. The low PD-L1 expression (negative rate of 79.5%) in pathological tissues indicates a limited population that may potentially benefit from immunotherapy. Additionally, 11.4% of patients have targetable mutations, among whom those with EGFR mutations or ALK rearrangements show favorable responses to targeted therapy. Molecular subtyping may have important guiding value for identifying the patient population who benefit from treatment for LCNEC.