Activity and immune correlates of PD-1 blockade therapy in advanced LCNEC patients.

Abstract Background : The efficacy of anti-PD-1 therapy in large-cell neuroendocrine carcinoma (LCNEC) patients remains unclear. We investigated the outcome of anti-PD-1 therapy and its predictive markers by evaluating the immune-related tumor microenvironment. Methods : We retrospectively reviewed advanced LCNEC patients treated with systemic chemotherapy. We also evaluated the PD-L1 expression (clone: 22C3), CD8-positive tumor-infiltrating lymphocytes (TILs), and the mutational profiles. Results : Seventy patients were enrolled, and 13 of the 70 patients received anti-PD-1 therapy. The progression-free survival (PFS) and the objective response rate (ORR) of the anti-PD-1 therapy were 4.2 months and 39%, respectively. The overall survival (OS) of patients treated with anti-PD-1 antibody (n = 13) was significantly better than those treated without anti-PD-1 antibody (n = 57) (25.2 vs. 10.9 months; p = 0.02). Among the 13 patients who were treated with anti-PD-1 antibody, 10 patients (90%) had PD-L1-negative tumors. Patients with a high density of tumoral CD8-positive TILs (≥38/mm2) had a significantly better ORR and PFS than those with a low density of tumoral CD8-positive TILs (ORR: p = 0.02, PFS: p = 0.003). Additionally, all three patients with a TP53 mutation co-occurring with a PIK3CA mutation (2 of the 8 patients) or the RB1 mutation (1 of the 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 advanced LCNEC patients.