Activity and Immune Correlates of Programmed Death-1 Blockade Therapy in Patients With Advanced Large Cell Neuroendocrine Carcinoma

We evaluated the efficacy of anti-programmed death receptor 1 (PD-1) therapy in patients with advanced large cell neuroendocrine carcinoma (LCNEC). Anti-PD-1 therapy was effective regardless of programmed death ligand 1 (PD-L1) positivity. The density of tumoral CD8-positive tumor-infiltrating lymphocytes and the presence of co-occurring mutations might be predictors of the efficacy of anti-PD-1 therapy in patients with advanced LCNEC. Background: The efficacy of anti-programmed death receptor 1 (PD-1) therapy in patients with large cell neuroendocrine carcinoma (LCNEC) remains unclear. We investigated the outcome of anti-PD-1 therapy and its predictive markers by evaluating the immune-related tumor microenvironment. Patients: We retrospectively reviewed patients with advanced LCNEC treated with systemic chemotherapy. We also evaluated PD ligand 1 (PD-L1) expression (clone: 22C3), CD8-positive tumor-infiltrating lymphocytes (TILs), and the mutational profiles. Results: Seventy patients were enrolled, and 13 of 70 patients received anti-PD-1 therapy. The progression-free survival (PFS) and objective response rate (ORR) of the anti-PD-1 therapy were 4.2 months and 39%, respectively. The overall survival of patients treated with anti-PD-1 therapy (n = 13) was significantly better than those treated without anti-PD-1 therapy (n = 57) (25.2 months vs 10.9 months; P = .02). Among the 13 patients treated with anti-PD-1 therapy, 10 patients (90%) had PD-L1-negative tumors. Patients with a high density of tumoral CD8-positive TILs ( >= 38/mm 2 ) had a significantly better ORR and PFS than those with a low density of tumoral CD8-positive TILs (ORR: P = .02; PFS: P = .003). Additionally, all 3 patients with TP53 mutation co-occurring with PIK3CA mutation (2 of 8 patients) or RB1 mutation (1 of 8 patients) responded to anti-PD-1 therapy. Conclusions: Anti-PD-1 therapy was effective regardless of PD-L1 positivity in patients with advanced LCNEC. Our investigation might suggest that the density of tumoral CD8-positive TILs and the presence of co-occurring mutations are predictors of the efficacy of anti-PD-1 therapy in patients with advanced LCNEC.