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F. Hirai



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    OA 13 - Immuno-Biology (ID 677)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      OA 13.06 - Co-Expression of IDO1 and PD-L1 Indicates More Aggressive Features of Lung Adenocarcinoma (ID 9672)

      11:00 - 12:30  |  Author(s): F. Hirai

      • Abstract
      • Presentation
      • Slides

      Background:
      Indoleamine 2, 3-dioxygenase 1 (IDO1) serves as an immunosuppressive effector and it is closely related to the prognosis in several types of cancer. We herein aim to elucidate the clinicopathological features and prognoses in patients with IDO1-expressing lung adenocarcinoma, and especially, show its correlation with the expression of programmed cell death-ligand 1 (PD-L1).

      Method:
      The expressions of IDO1 and PD-L1 proteins in 427 patients with surgically resected primary lung adenocarcinoma were evaluated by immunohistochemical analyses and any associations identified between IDO1 and the clinicopathological features, the prognosis and co-expression of IDO1 with PD-L1 were investigated. The expressions of IDO1 and PD-L1 at the protein and mRNA levels in lung adenocarcinoma cell lines were examined by an Enzyme-Linked Immuno Sorbent Assay, flow cytometry, and reverse transcription and real-time PCR analysis, respectively.

      Result:
      IDO1 was expressed in 260 patients (60.9%) at a 1% cut-off and in 63 patients (14.8%) at a 50% cut-off, respectively. PD-L1 was positive for 145 patients (34.0%). A ultivariate analysis showed IDO1 positivity (1% cut-off) to be significantly associated with a higher tumor grade, the presence of vascular invasion, and the expression of PD-L1. IDO1 and PD-L1 proteins were co-expressed in 123 patients (28.8%), and the patients whose tumor expressed both proteins exhibited significantly higher malignant traits than those whose tumor expressed only one protein or none. According to a multivariate analysis, the co-expression of both proteins was significantly associated with a shorter disease-free survival and overall survival. The expressions of IDO1 and PD-L1 in lung adenocarcinoma cell lines were elevated by treating them with interferon-γ and transforming growth factor-β.Figure 1



      Conclusion:
      The findings of this study suggest that the co-expression of IDO1 and PD-L1 may indicate more aggressive features of lung adenocarcinoma. Combination therapy targeting both of these proteins may therefore improve the clinical outcomes in patients with lung adenocarcinoma.

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    P1.03 - Chemotherapy/Targeted Therapy (ID 689)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P1.03-005 - Phase 2 Study of Ceritinib in Patients with ALK+ NSCLC with Prior Alectinib Treatment in Japan: ASCEND-9 (ID 8417)

      09:30 - 16:00  |  Author(s): F. Hirai

      • Abstract
      • Slides

      Background:
      ALK inhibitors are a standard of care for ALK-positive metastatic NSCLC and several ALK inhibitors are currently available. Alectinib is one of the recommended therapies as 1[st] line treatment for ALK-positive metastatic NSCLC in Japan based on robust progression-free survival (PFS) prolongation and favorable safety profile. However, even with treatment with alectinib, these cancers eventually progress after acquiring resistance against alectinib. Therefore, which drug should be chosen after alectinib is relevant clinical question. Recently, ceritinib, which is a highly selective oral ALK inhibitor, has demonstrated superior activity compared to chemotherapy in the 1[st] line setting for patients with ALK-positive metastatic NSCLC (ASCEND-4, Soria et al. Lancet 2017). It also showed clinically meaningful benefit in patients who failed to prior ALK inhibitor treatment including alectinib (Nishio et al. J Thorac Oncol 2015). In this study, we tried to evaluate efficacy and safety of ceritinib in ALK-positive metastatic NSCLC patients who progressed on alectinib treatment.

      Method:
      ASCEND-9 (NCT02450903) is a single-arm, open-label, multicenter, phase 2 study of ceritinib 750 mg/day (fasted) in adult patients with ALK+ (Vysis ALK Break Apart FISH Probe kit test), stage IIIB/IV NSCLC previously treated with alectinib and had subsequent disease progression. Other key inclusion criteria are ≥ 1 measurable lesion per RECIST 1.1 and WHO PS 0-1. Patients must have received previous treatment with alectinib, but prior crizotinib and/or up to 1 chemotherapy regimen are allowed. Patients with asymptomatic CNS metastases are eligible. Ceritinib may be continued beyond RECIST-defined PD. Primary endpoint is investigator assessed-overall response rate (ORR) per RECIST 1.1. Secondary endpoints include disease control rate (DCR), time to response (TTR), duration of response (DOR), PFS and safety. Biomarkers are evaluated for exploratory purpose.

      Result:
      Twenty patients were enrolled at 10 centers in Japan from Aug 2015 to Feb 2017. At present, the study is underway, and the results including ORR, DCR, TTR, DOR, PFS, safety and exploratory biomarker data will be presented at the 2017 WCLC.

      Conclusion:
      Section not applicable.

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    P1.07 - Immunology and Immunotherapy (ID 693)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P1.07-014 - Association of Preoperative Serum CRP with PD-L1 Expression in NSCLC: A Comprehensive Analysis of Systemic Inflammatory Markers (ID 8909)

      09:30 - 16:00  |  Author(s): F. Hirai

      • Abstract
      • Slides

      Background:
      Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have been approved as a standard therapy for metastatic non-small cell lung cancer (NSCLC). Although PD-L1 expression serves as a predictive biomarker for the efficacy of immunotherapy, there are no established biomarkers to predict the expression of PD-L1. The inflammatory markers C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) were recently shown to predict the efficacy of nivolumab for NSCLC patients. Therefore, here we investigated the potential association of PD-L1 expression with systemic inflammatory markers, including CRP, NLR, lymphocyte-monocyte ratio and platelet-lymphocyte ratio.

      Method:
      We retrospectively examined tumor PD-L1 expression in 508 surgically resected primary NSCLC cases by immunohistochemical analysis (cut-off value: 1%). The association of PD-L1 expression with preoperative systemic inflammatory markers was assessed by univariate and multivariate analyses. We generated a PD-L1 association score (A-score) from serum CRP level (cut-off value: 0.3 mg/dl) and smoking status to predict PD-L1 expression.

      Result:
      Among the total 508 patients, 188 (37.0%) patients were positive for PD-L1 expression at the 1% cut-off value and 90 (17.5%) had elevated serum CRP level. Multivariate logistic regression revealed that that PD-L1 positivity was significantly associated with advanced stage, the presence of vascular invasion and high serum CRP level (P=0.0336, 0.0106 and 0.0018, respectively). Though not significant, smoking history tended to be associated with PD-L1 protein expression (P=0.0717). There was no correlation with other inflammatory markers. Smoking history with elevated CRP level (A-score: 2) was strongly associated with PD-L1 protein expression (odds ratio: 5.18, P<0.0001), while it was inversely associated with EGFR mutation (odds ratio: 0.11, P<0.0001).

      Conclusion:
      Our results indicate that among all systemic inflammatory markers examined, serum CRP level could be a helpful biomarker for PD-L1 expression that is easily determined and available worldwide.

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    P2.09 - Mesothelioma (ID 710)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Mesothelioma
    • Presentations: 1
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      P2.09-005 - The C-reactive Protein/Albumin Ratio is a Novel Significant Prognostic Factor in Patients with Malignant Pleural Mesothelioma (ID 7375)

      09:30 - 16:00  |  Author(s): F. Hirai

      • Abstract
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is a devastating neoplasm. However, some patients show a good response to chemotherapy or multidisciplinary therapy. It is therefore important to investigate the factors that can be used to select patients who will benefit from such treatment. The C-reactive protein/albumin ratio (CAR) has been used to predict the prognosis in other diseases. The aim of this study was to elucidate the prognostic utility of the CAR in MPM patients.

      Method:
      The data of 83 patients, who were treated with surgery, chemotherapy, or multidisciplinary therapy at National Kyushu Cancer Center between 1995 and 2015, were analyzed in the present study. The CAR was calculated as C-reactive protein value divided by albumin value using the results of blood examination just prior to starting the treatments. A cut-off value of CAR was set to 0.58 according to the receiver operating characteristics (ROC) curve for 1-year-survival.

      Result:
      Thirty of the 83 (36.1%) patients were classified into the high CAR group. Twenty-seven (32.5%) and 56 (67.5%) patients underwent surgery and only chemotherapy, respectively. The ROC curve showed that the CAR had good diagnostic ability with 78.9% sensitivity and 68.0% specificity (AUC=0.761). A high CAR group was significantly correlated with advanced clinical stage (III/IV) (p=0.002) and chemotherapy alone (p=0.005). The high CAR group had significantly poorer overall survival (OS) (p<0.001) and disease or progression free survival (DFS/PFS) (p<0.001). The clinical stage and the CAR were independent predictive factors for the OS (I/II and III/IV, p=0.008; ≤0.58 and >0.58, p=0.034, respectively). The clinical stage and the CAR were also independent predictive factors for the DFS/PFS (I/II and III/IV, p=0.031; ≤0.58 and >0.58, p=0.019, respectively). In the subgroup analysis of the patients who underwent only chemotherapy, the high CAR group showed significantly poorer OS and DFS/PFS compared with the low CAR group (p=0.002 and p<0.001, respectively). However, the difference in OS and DFS/PFS of the patients who underwent surgery was not apparent between the high and low CAR groups (p=0.061 and p=0.187, respectively).

      Conclusion:
      The CAR was an independent predictor of a poor prognosis in the MPM patients. The high CAR group showed a significantly poorer prognosis in patients with MPM treated by only chemotherapy. This score provides useful information for selecting patients who will benefit from treatment, especially chemotherapy. These findings should be validated in further prospective studies.

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    P3.16 - Surgery (ID 732)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Surgery
    • Presentations: 1
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      P3.16-033 - Significance of Spread through Air Spaces in Resected Pathological Stage I Lung Adenocarcinoma (ID 9182)

      09:30 - 16:00  |  Author(s): F. Hirai

      • Abstract

      Background:
      Spread through air spaces (STAS) is a novel invasive pattern of lung cancer, which spreads within air spaces beyond the edge of the main tumor, but not necessarily accompanying stromal invasion. In the current study, we investigated the significance of STAS in patients with pathological stage I adenocarcinoma.

      Method:
      STAS was assessed in a total of 276 patients with resected pathological stage I adenocarcinoma. STAS was classified as either no STAS, low STAS (1-4 single cells or clusters of STAS), or high STAS (≥5 single cells or clusters of STAS) using a 20x objective and a 10x ocular lens. We evaluated the association between STAS and the clinicopathological characteristics and postoperative survivals.

      Result:
      Among 276 patients, 123 (44.6%), 48 (17.4%) and 105 (38.0%) were classified as having no, low and high STAS, respectively. Fisher’s exact test demonstrated that positivity for STAS was significantly associated with a larger radiological tumor diameter (P=0.008), a higher consolidation/tumor ratio (P<0.001), a higher maximum standard uptake value (P<0.001), a pathologically larger tumor size (P=0.004), the presence of pleural invasion (P=0.027) and a histologically invasive type (P<0.001), while STAS was not significantly associated with epidermal growth factor receptor mutations or programmed death ligand-1 expression (P=0.129 and P=0.872, respectively). Patients with the STAS had significantly shorter recurrence-free and overall survivals than those without (P<0.001 and P=0.002, respectively). According to a multivariate analysis, positivity for STAS remained an independent prognostic parameter for both the recurrence-free and overall survivals.

      Conclusion:
      STAS was associated with clincopathologically invasive features and was predictive of a worse survival. Figure 1