Lack of Association Between Immunotherapy and Improvement of Survival for Non-small Cell Lung Cancer Patients With Hemodialysis: A Nationwide Retrospective Cohort Study.

BACKGROUND: The number of patients undergoing hemodialysis continues to increase globally, and the incidence of cancer is high among these patients. Immune checkpoint inhibitors are widely used in patients with advanced cancer, especially non-small cell lung cancer (NSCLC); however, their effectiveness in hemodialysis patients is poorly documented. METHODS: This retrospective cohort study used data from a nationwide database. Patients diagnosed with NSCLC, undergoing hemodialysis, and who started chemotherapy between September 2008 and January 2023 were included. In the intention to treat (ITT) analysis, patients were divided into immune checkpoint inhibitor (ICI) and conventional chemotherapy group, and in the chronological analysis, patients were divided into 2 groups before and after ICI approval. Overall survival (OS) was analyzed using the Kaplan-Meier method with log-rank tests and Cox proportional hazards analyses. A propensity score approach was applied to address confounding factors, and analyses were performed by weighting each patient with the inverse of the estimated propensity score. RESULTS: We identified 322 and 389 patients in the ITT and chronological analyses respectively. In both analyses, there were no notable difference of OS between 2 groups (P values by log-rank test 0.933 and 0.248, respectively). The hazard ratios for OS were 0.980 (95% confidence interval [CI]: 0.678-1.415) in the ITT analysis and 0.805 (95% CI: 0.531-1.219) in the chronological analysis. CONCLUSION: The ICI treatment and approval were not significantly associated with improvement of survival in patients with NSCLC undergoing hemodialysis.

RBM17 Expression Is Associated With the Efficacy of ICI Monotherapy in NSCLC With Low PD-L1 Expression.

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) are currently a standard treatment tool for non-small cell lung cancer (NSCLC). RNA-binding motif protein 17 (RBM17), a splicing factor, is frequently over-expressed in NSCLC, but little is known about the role of RBM17 in the efficacy of ICIs for NSCLC. Thus, we investigated the correlation between RBM17 expression and ICI efficacy in NSCLC. PATIENTS AND METHODS: Biopsy or surgical specimens were collected from patients with advanced or recurrent NSCLC who received ICI monotherapy or chemo-immunotherapy in a first-line setting. RBM17 expression was examined using immunohistochemistry. The correlation between the efficacy of ICI monotherapy or chemo-immunotherapy and RBM17 expression was evaluated. RESULTS: Among the 218 cases, 115 (52.8%) cases were positive for RBM17 expression. RBM17 expression was not associated with the objective response rate (ORR) or progression-free survival (PFS) in either of the ICI monotherapy or chemo-immunotherapy groups. However, among those with a low PD-L1 expression level (PD-L1 <50%; n=86), RBM17 expression was significantly associated with a better ORR (p=0.045) and a better PFS (p<0.001) in the ICI monotherapy group, and was significantly associated with a poor ORR in the chemo-immunotherapy group (p=0.041). CONCLUSION: RBM17 might be a useful predictive marker for a higher efficacy of ICI monotherapy in NSCLC patients with a low PD-L1 expression level.

Clinical significance of KL-6 in immune-checkpoint inhibitor treatment for non-small cell lung cancer.

PURPOSE: Krebs von den Lungen-6 (KL-6) functions as a tumor marker, as well as a diagnostic tool for interstitial pneumonia (IP). However, the significance of KL-6 in the immune-checkpoint inhibitor (ICI) treatment of non-small cell lung cancer (NSCLC), especially in patients without IP, is unknown. METHODS: This multicenter, retrospective study, which included patients with advanced NSCLC who received ICI therapy, analyzed the association between serum KL-6 values and ICI efficacy and the association between serum KL-6 values and ICI-induced interstitial lung disease (ILD) occurrence, focusing primarily on patients without IP. RESULTS: In total, 322 patients had available KL-6 values before ICI therapy. Among 202 patients without IP who received ICI monotherapy, the high-KL-6 group (≥ 500 U/mL) showed significantly shorter progression-free survival (PFS) and overall survival (OS) than the low-KL-6 group (< 500 U/mL) (median: 2.1 vs. 3.6 months, p = 0.048; median: 9.2 vs. 14.5 months, p = 0.035). There was no significant difference in response rate between the KL-6 high and low groups (19% vs. 29%, p = 0.14). In the multivariate analysis, high KL-6 was a significant predictor of poor PFS (hazard ratio [HR], 1.52; 95% confidence interval [CI] 1.10-2.11, p = 0.012) and OS (HR, 1.51; 95% CI 1.07 - 2.13, p = 0.019) for patients treated with ICI monotherapy. There was no significant difference in the occurrence rate of ILD between the high KL-6 and low KL-6 groups in patients with (20% vs. 15%, p = 1.00) or without IP (12% vs. 12%, p = 1.00). CONCLUSION: In ICI monotherapy for NSCLC without IP, elevated serum KL-6 levels were associated with poorer outcomes.

Vimentin expression correlates with immune checkpoint inhibitor efficacy in non-small cell lung cancer.

BACKGROUND: Although vimentin is often expressed in non-small cell lung cancer (NSCLC), the association between vimentin expression and immune-checkpoint inhibitor (ICI) efficacy remains unclear. METHODS: This retrospective multicenter study enrolled patients with NSCLC who received ICI treatment between December 2015 and July 2020. The authors constructed tissue microarrays and performed immunohistochemical staining with vimentin. They analyzed the relationship between vimentin expression rate and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Immunohistochemically evaluable specimens on microarray blocks were available for 397 patients, of whom 343 (86%) were negative (<10%), 30 (8%) were positive (10%-49%), and 24 (6%) were highly positive (≥50%) for vimentin expression. Both rates of programmed death-ligand 1 (PD-L1) tumor proportion score ≥1% and ≥50% were significantly higher in the vimentin-positive group (≥10%) than the vimentin-negative group (<10%) (96% vs. 78%, p = .004; 64% vs. 42%, p = .006, respectively). In patients treated with ICI monotherapy, ORR, PFS, and OS were significantly better in the vimentin-positive group (10%-49%) than in the vimentin-negative group (<10%) (54% vs. 25%, p = .003, median = 7.9 vs. 3.2 months, p = .011; median = 27.0 vs. 13.6 months, p = .015, respectively), whereas there was no significant difference in PFS and OS between the vimentin highly positive group (≥50%) and the vimentin-negative group (<10%) (median = 3.4 vs. 3.2 months, p = .57; median = 7.2 vs. 13.6 months, p = .086, respectively). CONCLUSIONS: Vimentin expression correlated with PD-L1 expression and ICI efficacy. PLAIN LANGUAGE SUMMARY: We constructed tissue microarrays and performed immunohistochemical staining with vimentin on 397 patients with advanced non-small cell lung cancer who were treated with immune-checkpoint inhibitor (ICI). The vimentin-positive group who were treated with ICI monotherapy showed significantly better objective response rate, progression-free survival, and overall survival than the vimentin negative group. The measurement of vimentin expression will aid in determining appropriate immunotherapy strategies.

Influence of Smoking History on the Effectiveness of Immune-checkpoint Inhibitor Therapy for Non-small Cell Lung Cancer: Analysis of Real-world Data.

BACKGROUND/AIM: There is no real-world data in an Asian population to investigate the difference between the outcome of immune-checkpoint inhibitor (ICI) monotherapy and combination therapy for non-small cell lung cancer (NSCLC) based on smoking status. In this study, we investigated the correlation between smoking status and the efficacy of ICI therapy for NSCLC patients. PATIENTS AND METHODS: This multicentre retrospective study enrolled patients with recurrent or metastatic NSCLC who were treated using ICI therapy between December 2015 and July 2020. We analysed the objective response rate (ORR) of patients who received ICI monotherapy or combination therapy, based on smoking status using Fisher's exact test, and progression-free survival (PFS) and overall survival (OS) based on smoking status using the Kaplan-Meier method, the log-rank test, and Cox proportional hazards model. RESULTS: A total of 487 patients were included in the study. In the ICI monotherapy group, non-smokers showed significantly lower ORR and shorter PFS and OS than smokers (10% vs. 26%, p=0.002; median: 1.8 vs. 3.8 months, p<0.001; median: 8.0 vs. 15.4 months, p=0.026). In the ICI combination therapy group, non-smokers showed significantly longer OS than smokers (median: not reached vs. 26.3 months, p=0.045), and there was no significant difference in ORR and PFS between non-smokers and smokers (63% vs. 51%, p=0.43; median: 10.2 vs. 9.2 months, p=0.81). In the multivariate analysis of patients who received ICI combination therapy, the "non-smoker" status was not significantly associated with PFS [hazard ratio (HR)=1.31; 95% confidence interval (CI)=0.70-2.45, p=0.40] and OS (HR=0.40; 95% CI=0.14-1.13, p=0.083). CONCLUSION: Non-smokers showed worse outcomes than smokers with ICI monotherapy, but not with ICI combination therapy.

Tract creation with a 25-gauge needle for convex endobronchial ultrasound-guided core biopsy in intrapulmonary lesions adjacent to bronchi: three case reports.

Background: The use of endobronchial ultrasound-guided core biopsy (EBUS-CB) using forceps or cryoprobes to obtain true histological samples has improved the diagnostic yield for mediastinal and hilar lymphadenopathy. Tract creation in the bronchial wall of the central airway is primarily performed using electrocautery devices in EBUS-CB; however, their poor maneuverability and the risk of vascular injury and damage to the tip of the bronchoscope have prevented the application of EBUS-CB for diagnosing intrapulmonary lesions beyond the central locations. This report presents three cases wherein a 25-gauge transbronchial needle aspiration (TBNA) needle with high flexibility and safety was used to create a tract in the bronchial wall for EBUS-CB of the intrapulmonary lesions adjacent to the bronchi. Case Description: In all cases, EBUS-TBNA using a 25-gauge TBNA needle was performed on the intrapulmonary lesions adjacent to the bronchi, followed by EBUS-CB with 1.9-mm forceps in two cases and also with a 1.1-mm cryoprobe in one case. The EBUS-TBNA specimens revealed no abnormality or only a small number of tumor cells. However, subsequent EBUS-CB, through the tract created by EBUS-TBNA, enabled the collection of a sufficient amount of histological samples with well-preserved histoarchitecture. The histological diagnosis was made via immunostaining, and multigene mutation testing was also successfully analyzed. Conclusions: The use of a 25-gauge needle for creating a tract allows EBUS-CB for the intrapulmonary lesions and may allow for the collection of sufficient histological samples for biomarker analysis and tissue diagnosis.

Association of thyroid transcription factor-1 with the efficacy of immune-checkpoint inhibitors in patients with advanced lung adenocarcinoma.

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.

Vascular endothelial growth factor receptor 2 expression and immunotherapy efficacy in non-small cell lung cancer.

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.

SP142 evaluation contributes to the prediction of immune checkpoint inhibitor efficacy in non-small cell lung cancer with high PD-L1 expression assessed by 22C3.

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 immune-checkpoint 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 NSCLC with high PD-L1 expression assessed by 22C3.