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Background The association between the development of checkpoint inhibitor pneumonitis (CIP) with tumor response and survival has remained unclear so far. The aim of the present study was to evaluate the association between CIP and the clinical efficacy of anti‐programmed cell death‐1 antibody in patients with advanced non‐small cell lung cancer (NSCLC). Methods Between January 2016 and August 2019, 203 advanced NSCLC patients were administered with nivolumab or pembrolizumab. Comparisons were made between patients with and without CIP. We evaluated the time‐to‐treatment failure (TTF), progression‐free survival (PFS), and overall survival (OS). Results CIP was observed in 28 (14%) patients. CIP was associated with a longer PFS (18.9 months [95% confidence interval, CI: 8.7 months–not reached] vs. 3.9 months [95% CI: 3.4–5.1 months, p, This study aimed to evaluate the association between checkpoint inhibitor pneumonitis (CIP) and the clinical efficacy of anti‐programmed cell death‐1 monotherapy in patients with advanced non‐small cell lung cancer (NSCLC). CIP was associated with a longer PFS (18.9 months vs. 3.9 months, p

Background Anti-programmed cell death 1 antibody is a standard therapy for advanced non-small cell lung cancer (NSCLC). However, immune-related adverse events (irAEs), such as skin reactions, are frequently observed. Although skin reactions are associated with clinical efficacy in melanoma, this association in advanced NSCLC and predictors of irAEs remain unclear. Accordingly, this study identified potential correlations of skin reactions with clinical efficacy and clinical predictors of development of skin reactions. Subjects, Materials, and Methods We retrospectively surveyed patients with advanced NSCLC who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital (n = 155) during January 2016 to April 2018. Treatment efficacy was evaluated in patients with and without skin reactions, and associated predictive markers were determined. A 6-week landmark analysis was conducted to assess the clinical benefit of early skin reactions. Results Skin reactions were observed in 51 patients with a median time to onset of 6.4 weeks. The overall response rate (ORR) was significantly higher in patients with skin reactions (57% vs. 19%, p < .001). Median progression-free survival (PFS) durations of 12.9 and 3.5 months and overall survival durations of not reached and 11.4 months were observed in patients with and without skin reactions, respectively. In the 6-week landmark analysis, the ORR was significantly higher in patients with skin reactions, and skin reactions were significantly associated with increased PFS. A multivariate analysis identified pre-existing rheumatoid factor (RF) as an independent predictor of skin reactions. Conclusion Skin reactions appeared beneficial in patients treated with nivolumab/pembrolizumab for advanced NSCLC and could be predicted by pre-existing RF. Further large-scale validations studies are warranted.

Although anti-PD-1/PD-L1 monotherapy has achieved clinical success in non-small cell lung cancer (NSCLC), definitive predictive biomarkers remain to be elucidated. In this study, we performed whole-transcriptome sequencing of pretreatment tumor tissue samples and pretreatment and on-treatment whole blood samples (WB) samples obtained from a clinically annotated cohort of NSCLC patients (n = 40) treated with nivolumab (anti-PD-1) monotherapy. Using a single-sample gene set enrichment scoring method, we found that the tumors of responders with lung adenocarcinoma (LUAD, n = 20) are inherently immunogenic to promote antitumor immunity, whereas those with lung squamous cell carcinoma (LUSC, n = 18) have a less immunosuppressive tumor microenvironment. These findings suggested that nivolumab may function as a molecular targeted agent in LUAD and as an immunomodulating agent in LUSC. In addition, our study explains why the reliability of PD-L1 expression on tumor cells as a predictive biomarker for the response to nivolumab monotherapy is quite different between LUAD and LUSC.

Introduction: Immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events (irAEs). A correlation between the development of irAEs and efficacy has been suggested; however, it is unclear whether there is a relationship between programmed death ligand 1 (PD-L1) expression and the development of these events. Methods: We performed a retrospective study of advanced or metastatic non-small cell lung cancer (NSCLC) patients who were treated with pembrolizumab monotherapy at our institution between May 2015 and April 2018 (n = 44). Patients were categorized into two groups, specifically those with irAEs (irAE group) or without (non-irAE group), and we evaluated the objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Predictors of irAEs were examined by multivariate analysis. Results: irAEs of any grade occurred in 31 (70.5%) patients. The median PFS was 10.9 months in the irAE group versus 3.7 months in the non-irAE group (P < 0.001). ORR and DCR were also higher in the irAE group than in the non-irAE group. Furthermore, high PD-L1 expression (≥50%) was a predictive factor of irAE based on logistic regression (P = 0.004). Conclusions: In patients with advanced NSCLC treated with pembrolizumab monotherapy, ORR, DCR, and PFS were significantly better in the irAE group than in the non-irAE group. High PD-L1 expression, at the time of pretreatment, was identified as an independent predictor of irAE development. We believe that more careful management of irAEs for individuals with high PD-L1 expression is needed to improve clinical benefits. Further, PD-L1 expression might be useful for ICI risk management.

e21097 Background: Although anti-PD-1/PD-L1 monotherapy has achieved clinical success in non-small cell lung cancer (NSCLC), definitive predictive biomarkers remain to be elucidated. We assumed that by combining gene expression signatures with patient clinical data, we could identify a novel promising biomarker to predict response to anti-PD-1/PD-L1 monotherapy in NSCLC patients. Moreover, the characterization of these signatures will help us to decipher the complexity of tumor-immune interactions and better understand the tumor microenvironment (TME) that favors clinical response to nivolumab monotherapy. Methods: From clinically annotated NSCLC patients (n = 40) with nivolumab monotherapy in the second- or later-line settings, we prospectively collected tumor tissues and peripheral blood mononuclear cells (PBMCs) before first dose of nivolumab and PBMCs after first 4 or 5 doses of nivolumab. All tumor tissue and PBMC samples obtained were applied to whole-transcriptome sequencing (RNA-seq). We extracted transcriptomic datasets of lung adenocarcinoma (LUAD) (n = 20) and lung squamous cell carcinoma (LUSC) (n = 18) from the results, separately analyzed each histological subtype. To elucidate biological processes associated with clinical outcomes, we performed a supervised gene set enrichment analysis (GSEA) approach and an unsupervised single sample scoring approach. Results: In LUAD, we observed that gene sets related to interferon (type I and II) signaling (‘IFN signatures’) and antigen processing and presentation (‘APP signatures’) were significantly enriched in pre-treatment PBMCs of responders. IFN and APP signatures, which are closely related to each other, functionally cooperate to activate anti-tumor immune response. The enrichment of IFN and APP signatures provides the possibility that responders have a pre-existing anti-tumor immunity prior to nivolumab monotherapy. In LUSC, neither IFN nor APP signatures were enriched in pre-treatment tumor tissues and PBMCs of responders. Instead, gene sets related to the regulation of the TME (‘TME signatures’) are significantly enriched in pre-treatment tumor tissues of non-responders. The enrichment of TME signatures suggested that non-responders have an extremely immunosuppressive TME. These findings highlighted that responsive LUAD inherently have a high immunogenicity to elicit effective anti-tumor responses, whereas responsive LUSC have a similar level of immunogenicity as non-responsive LUSC but are free from an extremely immunosuppressive TME. Conclusions: We found that nivolumab enhanced anti-tumor immunity in patients with LUAD in a quite different way from patients with LUSC. Our study provides a blueprint for innovating combinational immunotherapy and supporting patient selection and treatment strategies on long-term clinical outcomes.

IMPORTANCE: Administration of anti–programmed cell death protein 1 (anti–PD-1) is now standard therapy in advanced non–small cell lung cancer (NSCLC). However, immune checkpoint inhibitors, including anti–PD-1, have not been assessed in patients with subclinical disease with advanced NSCLC, and no useful clinical biomarkers have been associated with immune-related adverse events (irAEs) among these patients treated with anti–PD-1. OBJECTIVE: To assess the safety and efficacy of anti–PD-1 treatment in patients with subclinical disease with advanced NSCLC and with or without preexisting autoimmune markers, including rheumatoid factor, antinuclear antibody, antithyroglobulin, and antithyroid peroxidase; and to assess potential clinical biomarkers that may be meaningfully and conveniently associated with clinical benefit or with irAEs following anti–PD-1 treatment. DESIGN, SETTING, AND PARTICIPANTS: This medical records analysis retrospectively evaluated 137 patients who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital in Japan between January 2016 and January 2018. Treatment efficacy and irAEs were evaluated along with candidate factors that may be associated with irAEs. EXPOSURES: Absence or presence of specific autoimmune markers and antibodies before treatment. MAIN OUTCOMES AND MEASURES: Preexisting antibodies and autoimmune markers, progression-free survival (PFS), and irAEs. RESULTS: Of 137 patients with advanced NSCLC, 105 were men, the median age was 68 (range, 36-88) years, 99 underwent nivolumab monotherapy, 38 underwent pembrolizumab monotherapy, and 134 had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median PFS was 6.5 (95% CI, 4.4-12.9) months among patients with examined preexisting antibodies and 3.5 (95% CI, 2.4-4.1) months among patients without, suggesting significantly better prognosis in the former. The hazard ratio for disease progression or death in the presence of the examined preexisting antibodies was 0.53 (95% CI, 0.36-0.79; P = .002). The PFS was significantly longer among patients with any preexisting antibodies than among those without. The examined preexisting antibodies (48 patients [73%]) and rheumatoid factor (26 patients [39%]) were more common among patients who developed irAEs. Multivariate analysis indicated that the presence of the examined preexisting antibodies was independently associated with irAEs (odds ratio, 3.25; 95% CI, 1.59-6.65; P = .001). Skin reactions were more frequent among patients with preexisting rheumatoid factor (47% vs 24%, P = .02), whereas thyroid dysfunction was more frequent among patients with preexisting antithyroid antibodies (20% vs 1%, P

Background Immune-related adverse events (irAEs) are frequently observed with nivolumab monotherapy. This study aimed to evaluate whether the development of irAEs correlates with treatment response in advanced non-small-cell lung cancer (NSCLC). Patients and Methods We conducted a retrospective study of patients who received nivolumab monotherapy at Sendai Kousei Hospital (n = 70). The patients were categorized into two groups based on the incidence of irAEs: those with irAEs (irAE group) or those without (non-irAE group). Treatment efficacy was evaluated in each group. The patients were further categorized into responders and nonresponders, and predictive factors of treatment response were determined. Results The objective response rate was 57% in the irAE group versus 12% in the non-irAE group. Median progression-free survival was 12.0 months in the irAE versus 3.6 months in the non-irAE group. The incidence of both irAEs and pre-existing antithyroid antibody was significantly higher in responders than in nonresponders. Multivariate analysis identified incidence of irAEs and pre-existing antithyroid antibody as an independent predictor of treatment response. Conclusion Objective response rate and progression-free survival were significantly better in the irAE than in the non-irAE group in patients with advanced NSCLC treated with nivolumab monotherapy. The development of irAEs was associated with clinical efficacy, and the presence of pre-existing antithyroid antibody might be correlated with treatment response to nivolumab monotherapy. Implications for Practice Immune-related adverse events (irAEs) are frequently observed with nivolumab monotherapy. This study evaluted whether the development of irAEs correlates with treatment response in advanced non-small-cell lung cancer. Results showed that the objective response rate and progression-free survival were significantly better in the patients who developed irAEs than in the patients who did not develop irAEs, and the incidence of irAEs and positivity for antithyroid antibody at pretreatment were independent predictors of treatment response of nivolumab monotherapy. Therefore, the development of irAEs predicts clinical benefit and suggests that cautious management of irAEs can lead to achieving maximum clinical benefit from nivolumab monotherapy.

Diarrhea post-antibiotic use is primarily attributed to Clostridium difficile infection (CDI)-induced mucosal lesions, and evidence of CDI in patients undergoing chemotherapy without prior antibiotic treatment is also increasing. However, few studies have investigated the relationship between chemotherapy use and diarrhea. This study aimed to determine whether the incidence of CDI increased in patients with lung cancer undergoing chemotherapy even without prior antibiotic treatment. We conducted a retrospective study and investigated the presence of Clostridium difficile (C. difficile) and its toxins in patients who experience diarrhea during chemotherapy. If grade 2 or higher diarrhea was noted, a stool culture was performed to detect anaerobic organisms and C. difficile toxins A and B. A total of 345 consecutive patients (492 in terms of chemotherapy regimens) were enrolled in the study. Grade 2 or higher diarrhea was observed in patients using 36 (7.3%) of these regimens, among which CDI without prior antibiotic exposure was confirmed in patients using 8 regimens (22.2%). CDI may remain undetected in patients undergoing chemotherapy even in those who had not received antibiotic treatment previously, unless due attention is paid to its possibility. Testing for C. difficile toxins is highly recommended to expedite timely treatment for diarrhea in such patients. Further studies are needed to clarify the relationship between chemotherapy drug use and CDI to facilitate prevention.

近年注目されている複雑ネットワークには，代表的なモデルとして，スモールワールドネットワークとスケールフリーネットワークがある．本研究では，新規ノードの結合に類似度に基づく優先選択を取り入れた制約を与え，成長させながらネットワークを構成する手法を提案する．提案手法は自己組織化マップのアルゴリズムを参考に，より自然なネットワークの生成及び，現実のネットワークの特徴を示すネットワークの生成を目的としている．提案手法で生成したネットワークは小さい平均頂点間距離（L）及び，大きいクラスター係数（C）を示し，次数分布はべき則に従うという結果が得られた．また本手法により生成されたネットワークは，べき則を満たすにも関わらず，次数の高いハブノードから受ける影響が小さく，現実のネットワークに見られるような頑強性を示すという結果が得られた．