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N. Yang



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    P1.01 - Advanced NSCLC (ID 757)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P1.01-035 - A Next Generation Sequencing and Characteristics Based Model for Predict Clinical Benefit  of Advanced NSCLC Patients (ID 9208)

      09:30 - 09:30  |  Author(s): N. Yang

      • Abstract

      Background:
      The development of targeted therapies has revolutionized the treatment of non-small cell lung cancer. Interrogating the status of driver mutations has become routine practice. In this study, we applied next-generation sequencing to investigate the association between molecular signature and clinical benefit.

      Method:
      We performed capture-based targeted ultra-deep sequencing on 204 samples obtained from NSCLC patients at a single center, including 93 FFPE, 70 fresh tissue and 41 plasma samples. One hundred and twenty two samples were subjected to a panel consisting of 8 driver genes; 50 samples were subjected to a 56-gene panel. The remaining 32 samples were subject to a 168 gene panel.

      Result:
      In 159 TKI-naïve patients, driver mutation was identified in 95.2% of (79/83) patients using the 8-gene panel; among them, 65.1% (54/83) carried EGFR mutations. Larger panels identified mutations in 68.1% of patients; 21% carried mutations other than driver mutations. Treatment-naïve patients were primarily subject to the 8-gene panel; in contrast, patients progressed on chemotherapy were subject to larger panels. Seventy-two percent of patients (80/111) undergone matched targeted therapy (MTT) according to sequencing results had a significantly longer PFS than 29 patients who chose chemotherapies despite the fact of harboring driver (p=4.58x10[-4] HR=0.342, 95% CI: 0.158, 0.74). Next, we investigated whether the number of EGFR mutations a patient carries and the presence of concurrence EGFR amplification have an effect on PFS. Our data revealed that both parameters are not associated with PFS. Among 46 patients receiving chemotherapy, patients with KRAS mutations were associated with a shorter PFS, 133 days vs 207 days (p= 0.073, HR=2.06 95% CI; 0.791, 5.36). For TKI-naïve patients, primary tumor tissue was collected from 86 patients and tumor tissue from metastatic lymph nodes was collected from 35 patients. Interestingly, we observed that lymph node samples had a higher maximum mutation allelic fraction (MAF) than primary lung tumor samples in patients with distance metastasis, especially with visceral metastasis (p=0.0986); such trend was not observed in patients without distant metastasis. We also analyzed samples obtained after TKI-treatment. Among 36 TKI-treated patients, patients with visceral metastasis were more likely to harbor TP53 mutations (p=0.04), which were primarily missense mutations not loss of function mutations, primarily seen in tumorigenesis. TP53 missense mutations can potentially promote distant visceral metastasis after the development of resistance to TKIs.

      Conclusion:
      Our study highlighted the utility of sequencing-based screening technologies and characteristics in providing treatment guidance.

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    P1.04 - Clinical Design, Statistics and Clinical Trials (ID 690)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      P1.04-009 - The First Study of BBSKE in Heavy Treated Advanced EGFR Wild Type and ALK Negative, Trxr1 High Expression NSCLC Patients. (ID 8493)

      09:30 - 09:30  |  Author(s): N. Yang

      • Abstract

      Background:
      Thioredoxin reductase plays a critical role in cell metabolism. According to our previous study, The expression of TrxR1 was significantly higher in serum of tumor patients than in heathy volunteers and approximately 50% of non-small cell lung cancer patients harbored high thioredoxin reductase expression. EGFR and ALK negative patients with high expression of TrxR1 responded poorer to chemotherapy. Ethaselen, a potent mammalian thioredoxin reductase 1 inhibitor was applied to address the heavy treated EGFR and ALK negative NSCLC with high thioredoxin reductase expression.

      Method:
      We plan to recruit 40 EGFR wild type and ALK negative metastatic non small cell lung cancer patients who have received at least 2 lines of standard therapy, performance status as 0-2 and with high TrxR1 IHC expression. It is a single arm project and all patients receive the treatment of BBSKE 1200mg PO QD until disease progression according the Response Evaluation Criteria in Solid Tumor 1.1(RECIST 1.1) or intolerable toxicity or withdraw from the study. The primary endpoint is 8 weeks Disease Control Rate and the anticipated rate is over 20%. Test of TrxR1 Serum activity is mandatory and performed by a central laboratory at the Medical Center of Casis. There will be several times of dynamic testing, from baseline to parallelly go along with each RECIST Evaluation, so as to draw some correlation between the change of TrxR1 expression and imaging. This program has been registered at clinicaltrials.gov and the number is NCT02166242.

      Result:
      Section not applicable

      Conclusion:
      Section not applicable

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    P2.15 - SCLC/Neuroendocrine Tumors (ID 716)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      P2.15-001 - NHWD-870, a Novel BET Family Bromodomain Inhibitor Targeting BRD2/3/4, Proved to Be Effective and Promising for Treatment of Small Cell Lung Cancer (ID 8650)

      09:30 - 09:30  |  Author(s): N. Yang

      • Abstract

      Background:
      Small molecule inhibitors targeting bromodomain and extraterminal domain (BET) protein is promising for cancer therapy. According to our previous study, BRD4 was highly expressed in small cell lung cancer (72%) and correlated with poor prognosis.

      Method:
      Series small molecular compound NHWD which design and modify by ourselves is a potent and selective BET family bromodomain inhibitor and only binds bromodomains of BRD2/3/4/T. We use the MTT in small cell lines to evaluate the activity and selected the best. And then potential pathway was demonstrated with Western blot and low cytometry. Finally, the activity of small compounds was conducted by xenograft and Patient Derived Xenograft (PDX).

      Result:
      Compare with JQ1 and other molecular compounds, NHWD-870 has the best effectiveness and powerful anti-cancer, and the IC50 was 1.579nM (figure 1). NHWD-870 exhibited robust single agent activity in cell viability assay across cell lines in vitro and xenografts of small cell lung cancer in vitro by downregulating the PDGFRβ, MEK1/2 and STAT1/MYC pathway (figure 1). Consistent with its broad spectrum of activities in invo, NHWD-870 has potent tumor suppressive efficacies in PDX model of small cell lung cancer (figure 2).Figure 1Figure 2





      Conclusion:
      Further research will be conducted about series small molecular compounds from bench to beside.