Abstract:

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.

Key words: Pulmonary large cell neuroendocrine carcinoma, Targeted therapy, Gene mutation