Background We aimed to identify the relationship between thyroid transcription factor‐1 (TTF‐1) expression of lung adenocarcinoma and the efficacy of immune‐checkpoint inhibitor (ICI) therapy. Methods This retrospective multicenter study comprised patients with advanced lung adenocarcinoma treated with ICI monotherapy. We collected clinical medical records including data on TTF‐1 expression and analyzed the relationship between TTF‐1 expression and programmed death‐ligand 1 tumor proportion score (PD‐L1 TPS), objective response rate (ORR), progression‐free survival (PFS), and overall survival (OS). Results In total, 108 patients with lung adenocarcinoma were analyzed. The rate of TPS ≥1% and ≥50% in patients with positive TTF‐1 expression was significantly higher than that in patients with negative TTF‐1 expression (88% vs. 60%, p < 0.001; 65% vs. 24%, p < 0.001). The ORR was significantly higher in TTF‐1 positive patients than in TTF‐1‐negative patients (38% vs. 8%, p = 0.003). Among patients with TPS ≥50% and 1%–49%, the ORR in TTF‐1 positive and negative patients was 48% (26/54) versus 17% (1/6) ( p = 0.21), and 32% (6/19) versus 11% (1/9) ( p = 0.37), respectively. The ORR for patients with TPS <1% was 0% in both the TTF‐1 negative and positive cases. The median PFS and OS was significantly longer in TTF‐1‐positive patients than in TTF‐1‐negative patients (5.4 vs. 1.6 months, p < 0.001; 18.2 vs. 8.0 months, p = 0.041). Multivariate analysis revealed that TTF‐1‐negative status was an independent unfavorable prognostic factor for PFS. Conclusion Patients with TTF‐1‐positive status receiving ICI monotherapy showed better outcomes than those with TTF‐1‐negative lung adenocarcinoma.

It is unclear whether tumor vascular endothelial growth factor receptor 2 expression affects the therapeutic efficacy of immune‐checkpoint inhibitors and antiangiogenic agents. This retrospective, multicenter study included patients with advanced non–small cell lung cancer who were treated with immune‐checkpoint inhibitors. We constructed tissue microarrays and performed immunohistochemistry with an anti‐vascular endothelial growth factor receptor 2 antibody. We analyzed immune and tumor cell staining separately in order to determine their correlation with the objective response rate, progression‐free survival, and overall survival in patients receiving immune‐checkpoint inhibitors. Of 364 patients, 37 (10%) expressed vascular endothelial growth factor receptor 2 in immune cells and 165 (45%) in tumor cells. The objective response rate, progression‐free survival, and overall survival were significantly worse in patients treated with immune checkpoint inhibitor monotherapy who expressed vascular endothelial growth factor receptor 2 in immune cells than those who did not (10% vs 30%, p = 0.028; median = 2.2 vs 3.6 months, p = 0.012; median = 7.9 vs 17.0 months, p = 0.049, respectively), while there was no significant difference based on tumor cell expression (24% vs 30%, p = 0.33; median = 3.1 vs 3.5 months, p = 0.55; median = 13.6 vs 16.8 months, p = 0.31). There was no significant difference in overall survival between patients treated with and without antiangiogenic agents in any treatment period based on vascular endothelial growth factor receptor 2 expression. Immune checkpoint inhibitor efficacy was limited in patients expressing vascular endothelial growth factor receptor 2 in immune cells.

Background: It remains unclear whether assessing programmed death-ligand 1 (PD-L1) expression by SP142 plus 22C3 adds value for predicting the response to immunotherapy in non-small cell lung cancer (NSCLC).Methods: This retrospective multicenter study included patients with advanced NSCLC treated with immune-checkpoint inhibitors. We constructed tissue microarrays (TMAs) and performed immunohistochemical staining with 22C3 and SP142 assays. We denoted the PD-L1 tumor proportion score (TPS) obtained from clinical medical records based on 22C3 staining as "22C3 (C)" and that obtained with 22C3 staining using our TMA as "22C3 (TMA)". SP142 staining was evaluated in both tumor cells and immune cells. We assessed the concordance between each PD-L1 assessment method and analyzed the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) based on the PD-L1 expression level determined using the 22C3 and SP142 assays.Results: In total, 288 patients were included. Among those with 22C3 (TMA) ≥50%, 60% of patients showed SP142 TC3 or IC3; among patients with 22C3 (C) <1%, 9% and 18% exhibited 22C3 (TMA) ≥1% and SP142 TC1/2/3 or IC1/2/3, respectively. Among patients with 22C3 (C) ≥50% treated with immunecheckpoint inhibitor monotherapy, the SP142 TC1/2/3 or IC1/2/3 group showed significantly better ORR, PFS and OS than the SP142 TC0 and IC0 group (54% vs. 29%, P=0.040, median =11.0 vs. 3.2 months, P=0.002, median =27.9 vs. 12.6 months, P=0.030, respectively). Multivariate analysis revealed that SP142 TC0 and IC0 was an independent unfavorable prognostic factor for PFS and OS in patients with 22C3 (C) ≥50% treated with immune-checkpoint inhibitor monotherapy. For those with 22C3 (C) ≥50% and SP142 TC0 and IC0, immune-checkpoint inhibitor concurrent with chemotherapy tended to result in a longer PFS and OS than immune-checkpoint inhibitor monotherapy (median =13.7 vs. 2.3 months, P=0.054, median = not estimable vs. 12.0 months, P=0.064, respectively).Conclusions: SP142 evaluation contributes to the prediction of immune-checkpoint inhibitor efficacy in ^ ORCID: 0000-0001-7423-6153.NSCLC with high PD-L1 expression assessed by 22C3.