The survival analysis of stage III and IV inoperable lung large cell neuroendocrine carcinoma and the role of LIPI in immunological stratification

Large cell neuroendocrine carcinoma (LCNEC) represents a rare and unique type of lung tumor with an unfavorable prognosis. It is essential to summarize the treatment modalities and prognosis for inoperable stage III and IV LCNEC, explore the role of frontline immunotherapy, and examine the stratification role of the Lung Immune Prognostic Index (LIPI) and its relationship with the tumor microenvironment (TME). This study retrospectively analyzed 160 patients with inoperable lung LCNEC (L-LCNEC) admitted to three hospitals from December 2012 to November 2023. We evaluated the effects of different systemic treatment modalities on prognosis and explored independent prognostic factors, establishing models incorporating blood indicators. Furthermore, the study aimed to assess the association of the LIPI with overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in patients receiving immune checkpoint inhibitors (ICIs). Patients receiving frontline immunotherapy had significantly higher ORR (52.0 % vs. 24.7 %, p < 0.001), PFS (6.33 vs. 2.93 months, p = 0.033) and OS (21.3 vs. 12.9 months, p = 0.034). Independent protective factors for OS included frontline immunotherapy (p = 0.008) and CK positive expression (p = 0.033), while poor LIPI (p = 0.023), ≥3 metastatic sites (p = 0.005), positive CgA expression (p = 0.016), and DD-2 ≥ 5.0 (p < 0.001) were identified as independent risk factors. A prognostic model based on these factors had an AUC of 0.749. Significant differences in median PFS (mPFS) and median OS (mOS) were observed among the good, intermediate, and poor LIPI groups (p < 0.05). Multiple immunofluorescence staining revealed that the good LIPI group exhibited greater infiltration of immune cells marked by CD3 antibody. This study highlights the benefit of frontline immunotherapy and the importance of LIPI in prognosis stratification, especially in identifying patients with limited treatment benefit.