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J. Wang



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    MTE09 - Biomarkers for Targeted Therapies and Immune Checkpoint Inhibitors in Advanced NSCLC (Ticketed Session) (ID 303)

    • Event: WCLC 2016
    • Type: Meet the Expert Session (Ticketed Session)
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 12/05/2016, 07:30 - 08:30, Stolz 1
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      MTE09.01 - Biomarkers for Targeted Therapies and Immune Checkpoint Inhibitors in Advanced NSCLC (ID 6554)

      07:30 - 08:00  |  Author(s): J. Wang

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The targeted therapy based on genotyping has become an important treatment approach for advanced non-small cell lung cancer (NSCLC), especially adenocarcinoma. It is reported that nearly fifty to sixty percent of Asian patients with lung adenocarcinoma could have survival benefit from the first generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) and Anaplastic Lymphoma kinase (ALK)-TKI. However, the targeted therapy has apparently reached a plateau due to the drug resistance. The spatial and temporal heterogeneity of tumors are regarded as the foundation of both primary and acquired resistance. Multiple studies show that the mechanism of acquired resistance to first generation EGFR-TKI is complicated, including T790M mutation, PI3KCA mutation, c-MET amplification, and histologic transformation from NSCLC to SCLC et al, some of which could co-exist in the same patient. Although the third generation EGFT-TKI targeted at T790M mutation has been proved with dramatic efficacy, most patients become resistant after 10 months of therapy, the mechanism of which is even more complicated. Recently, by conducting next generation sequencing (NGS) through peripheral blood samples of patients treated with AZD9291 and CO1686 in clinical trials, newly drug-resistant mutations such as C797S and C693I have been found and functionally verified. This has laid a solid foundation for developing the fourth generation medicine in future undoubtedly. In the meanwhile, the resistant mechanism to ALK-TKI is also very complex. Multiple drug-resistant mutations could not only occur in ALK kinase domain, but also in alternative signal pathways. Therefore, we should establish a real-time, dynamic and quantitative detecting system for multiple targetable genes to fulfill detecting and monitoring the drug resistance during treatment, and on the other hand, to explore novel drug-resistant mutations through NGS of peripheral blood samples in future. Checkpoint inhibitors have been studied and utilized in various cancers, which has changed the perennially stagnant situation of immunotherapy and opened a new chapter in the treatment of cancers. Studies have shown an objective response rate of approximately 20%-30% with a prolonged survival period of 3-6 months to a series of programed death (PD1)/ programed death-ligand 1(PD-L1) inhibitors immunotherapy in lung cancer patients, with adenocarcinomas, squamous cell carcinomas and small cell carcinomas. While the biggest challenge of immunotherapy currently is to establish a powerful predictive system for efficacy. The existing researches mostly focus on exploring whether the PD-L1 expression or tumor infiltrating lymphocytes (TIL) status could predict the efficacy of PD1/PD-L1 inhibitors. The results varied from different agents of PD1/PD-L1 inhibitors and results of different trails. For instance, PD-L1 expression was associated with response to Nivolumab in patients with lung adenocarcinoma, while this kind of relationship was not observed in squamous cell NSCLC. The inconsistency between different trails may be attributed to the heterogeneity of PD-L1 expression, the unstandardized sample collecting and storing, and issue in IHC evaluation system. So the future investigation should lay more emphasis on overcoming tumor heterogeneity, standardization and optimization of detection techniques and sample collections, based on which we are looking forward to more effective predictive biomarkers. Both tumor and host microenvironment should be equally important as the foundation of precision medicine for cancer. More and more studies show that mutation loads of somatic cells contribute to immunogenicity of tumors, so as to be associated with the efficacy of checkpoint inhibitors. One research showed that different types of mutations, such as EGFR mutation, ALK fusion gene and PI3KCA mutation, possess different levels of mutation loads. And another research indicated that lung adenocarcinoma with higher neoantigen-load responded better to checkpoint inhibitors than the lower ones. There has been a study to calculate mutation loads and neoantigens in adenocarcinoma or squamous carcinoma by whole Exome sequencing based on the Cancer Genome Atlas (TCGA). The future studies should pay close attention to exploring the dynamic change patterns of mutation loads and neoantigens prior and during the treatment strategies, including PD-1/PD-L1 inhibitors immunotherapy, targeted therapy and traditional chemotherapy, and also to investigate the relationship between regulatory immune factors in the microenvironment, to further establish the predictive system for immunotherapy integrating PD-L1、PD-L2, TIL mutation loads of somatic cells, and neoantigens which are in great expectations.

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    OA11 - Angiogenesis in Advanced Lung Cancer (ID 387)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA11.03 - A Randomized, Multi-Center, Double-Blind Phase II Study of Fruquintinib in Patients with Advanced Non-Small Cell Lung Cancer (ID 4571)

      11:10 - 11:20  |  Author(s): J. Wang

      • Abstract
      • Presentation
      • Slides

      Background:
      Targeting the tumor microenvironment, such as tumor angiogenesis, has led to the successful development and approval of a number of targeted therapies thereby changing the standard of care for many types of cancer. However, treatment options are limited in third-line non-small cell lung cancer (NSCLC) patients. Fruquintinib is a potent and highly selective oral kinase inhibitor targeting vascular endothelial growth factor receptors and is currently in late stage development for multiple cancers. This Phase II study was designed to evaluate the efficacy and safety of fruquintinib in third-line NSCLC patients (NCT02590965).

      Methods:
      A total of 91 patients were randomized to receive best supportive care (BSC) plus fruquintinib or BSC plus placebo in a 2:1 ratio from 12 Chinese clinical centers. Fruquintinib initial dose was 5 mg once daily and treatment was given in every 4-week cycle (3 weeks treatment followed by 1 week off). The primary objective was to compare progression free survival (PFS) between the two treatment groups. Secondary efficacy parameters included objective response rate (ORR), disease control rate (DCR), overall survival (OS). Tumor response was assessed per RECIST 1.1.

      Results:
      As of August 7, 2015, median PFS was 3.8 months for the fruquintinib group comparing with 1.2 months for the placebo group (hazard ratio=0.27, p<0.001). The ORR was 16.4% for the fruquintinib group comparing with 0% for the placebo group (p=0.02). The DCR of the fruquintinib group was significantly higher than that of the placebo group with a difference of 53.8% (36.3, 71.4; 95% CI, p<0.001). OS was not mature and initial analysis revealed 3- and 6-month OS rates of 90.2% and 68.3% for the fruquintinib group, and 73.3% and 58.2% for the placebo group, respectively. Adverse event was reported in 68.9% and 60.0% patients in fruquintinib and placebo group, respectively. The incidence of serious adverse events was 3.3% in the fruquintinib group and 6.7% in the placebo group.

      Conclusion:
      Fruquintinib in third-line NSCLC met the primary efficacy endpoint of PFS and demonstrated superiority in the secondary endpoints of ORR and DCR as compared with placebo. OS has yet to mature. Fruquintinib was generally well tolerated and safety profile consistent with previously reported. These results support further development of fruquintinib in third-line NSCLC patients. A randomized, double-blind, multi-center Phase III registration study was initiated in December 2015 (NCT02691299). Clinical trial information: NCT02590965.

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02b-118 - Potential Mechanism Revealed by Targeted Sequencing from Lung Adenocarcinoma Patients with Primary Resistance to EGFR-TKIs (ID 6236)

      14:30 - 14:30  |  Author(s): J. Wang

      • Abstract

      Background:
      Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKIs) has greatly improved the prognosis of lung adenocarcinoma. However, there are still approximately 20% lung adenocarcinoma patients with EGFR sensitive mutations that were primary resistance to EGFR-TKIs treatment The underlying mechanism is unknown.

      Methods:
      This study explored the mechanisms of primary resistance by analyzing 11 paired patients with corrsponding primary resistance (PFS<3months or without objective response) and sensitivity(PFS>12months)to EGFR-TKIs by next-generation sequencing (NGS). NGS targeted sequencing was performed on the Illumina X platform for 483 cancer-related genes. EGFR mutation was detected by ARMS initially.

      Results:
      Potential primary resistance mechanism was revealed by high frequency mutations unique in EGFR-TKIs resistance group. Among the 11 patients, 54.55% (6/11) carried known resistance mechanism, (2 patients carried MET amplification; 2 patients carried T790M mutation; 1 patient carried Her2 amplification; 1 patient carried PTEN loss). And 45.45%(5/11) carried novel mutations that may lead to drug resistance (2 patients carried TGFBR1 mutation; 1 patient carried TMPRSS2 fusion gene; 1 patient both have BIM deletion polymorphism and EGFR uncommon mutation). By analyzing somatic single-nucleotide mutation patterns, we found the frequency of C:G→T:A transitions in primary resistance group was significantly higher than that in sensitive group(0.54 vs 0.39, P=0.012).

      Conclusion:
      The mechanism of EGFR-TKIs primary resistance is sporadic. TGFBR1 mutation, TMPRSS2 fusion gene and EGFR multiple mutations might be associated with EGFR-TKIs primary resistance. Cytosine spontaneous deamination (C:G→T:A)was positively associated with EGFR-TKIs primary resistance.