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Hyun Ae Jung



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    MA08 - Pawing the Way to Improve Outcomes in Stage III NSCLC (ID 127)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
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      MA08.03 - Adjuvant Pembrolizumab in N2 Positive NSCLC Treated with Concurrent Chemoradiotherapy Followed by Surgery: Phase II, Prospective Study (Now Available) (ID 1744)

      15:15 - 16:45  |  Author(s): Hyun Ae Jung

      • Abstract
      • Presentation
      • Slides

      Background

      The standard treatment option for stage IIIA-N2 subgroup is still under discussion with controversies. We hypothesize that immune checkpoint inhibitor consolidation therapy could have an additional role in prolongation of the disease-free survival (DFS) for stage IIIA-N2 NSCLC treated with tri-modalities therapy.

      Method

      This is a phase 2 study evaluating the clinical efficacy of pembrolizumab treatment after CCRT with curative resection in stage IIIA-N2 NSCLC pts (NCT03053856). Pathologically confirmed pts were treated with five cycles of CCRT, weekly paclitaxel (50mg/m2) and cisplatin (25mg/m2) combined with radiotherapy (total of 44Gy over 22 fractions) followed by curative resection. Adjuvant Pembrolizumab (200mg fixed dose) is applied every three weeks up to 2 years or until disease recurrence. The primary objective is disease-free survival of more than 20 months. The first patient was recruited in October 2017, and the data for this abstract was locked at 20th of January, 2019.

      Result

      Total of 40 pts were screened, and 37 pts received treatment. Median age was 64 years (range 39-74), and twenty-three pts were male (62.2%). As a curative surgery, pts received lobectomy (n=34), bi-lobectomy (n=2), or pneumonectomy (n=1). Adenocarcinoma was predominant (n=27, 73.0%). After the neoadjuvant CCRT, down-staging were observed in nine pts (24.3%). The median follow-up duration was 10.6 months (range 3.1-17.2), and pts received a median of 11 cycles (range 1-22) of adjuvant pembrolizumab. DFS is not reached. Fourteen patients discontinued treatment due to disease progression (n=9), adverse events (n=4) and withdraw consent (n=1). There was a case of grade 4 pneumonitis and a case of grade 3 autoimmune hepatitis which lead to discontinuation of the treatment. Otherwise, grade 1-2 hypothyroidism (n=6), pneumonitis (n=5), skin rash (n=3) were observed. Patients with severe immune-related adverse event showed a significantly high percentage of Ki-67 + cells among CD8 T-cells in peripheral blood.

      Conclusion

      This study is the first study to demonstrate the feasibility of adjuvant pembrolizumab monotherapy in stage IIIA-N2 patients. Updated clinical outcome will be presented at the conference.

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    MA19 - Looking at PROs in Greater Detail - What Patients Actually Want and Expect (ID 147)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Now Available
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      MA19.06 - Successful Development of Realtime Automatically Updated Data Warehouse in Health Care (ROOT-S) (Now Available) (ID 584)

      11:30 - 13:00  |  Presenting Author(s): Hyun Ae Jung

      • Abstract
      • Presentation
      • Slides

      Background

      Clinical information is often not recorded in an organized way, and converting it to a structured format can be a time-consuming task that may not successfully capture all facets of the information. Clinical Data Warehouse is a real time database that consolidates data from a variety of clinical sources to present a unified view. However, the clinical data extracted from the CDW have not only structured data (SD) but also natural language (NP) generated during clinical practice, and there is a limitation that it is difficult to apply to clinical trials because it is not structured and formatted to find key-point contents. This study aims at developing a systematic and comprehensive cohort through an automatic real-time update system called CDW.

      Method

      The aim of this study was to evaluate clinical data of non-small cell lung cancer, small cell lung cancer, head and neck cancer, thymic cancer, and mesothelioma. In this study, we developed a unique algorithm that is optimized for each disease category using comprehensive natural language processing (NLP) systems and structured information from unstructured free text and structured data capture (SDC). We developed an algorithm using clinical information of patients diagnosed and treated during the past 10 years and designated validation sets of patients diagnosed and treated in 2018 for validation that these algorithms work automatically.

      Result

      We collected clinical data of 23,735 NSCLC patients, 2,077 SCLC patients, 5,032 head and neck cancer patients, 3,948 esophageal cancer patients, 747 thymic cancer patients and 138 mesothelioma patients diagnosed at Samsung Medical Center. We could demonstrate using the validation set that the program accurately extracts the data needed for the cohort of each cancer. The program is updated automatically every 24 hours, the source of each data is indicated separately, and the data that need to be integrated is transformed and systematically organized. The biggest advantage is that the scattered information is systematically integrated and automatically buildup to match the patient's cohort, so you can capture most updated survival or test results or treatment outcomes almost in real time. Data on the development of this program will be presented.

      Conclusion

      This study is the first study that successfully developed and validated real-time updated cohort using CDW. This study suggests a blueprint for constructing a big data -based cohort for clinical research and is expected to be a landmark trial. The detailed analysis of each cancer through the development of the program will be presented.

      wclc.png

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    MA21 - Non EGFR/MET Targeted Therapies (ID 153)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA21.10 - Phase II Study of 160mg of Osimertinib in EGFR T790M Positive NSCLC with Brain or Leptomeningeal Metastases Who Progressed on Prior EGFR TKI (Now Available) (ID 1705)

      14:30 - 16:00  |  Author(s): Hyun Ae Jung

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR tyrosine kinase inhibitor (TKI) has successfully improved clinical outcome in non-small cell lung cancer (NSCLC) with activating EGFR mutation. However, up to 40% of TKI treated patients present with disease progression in the central nerve system (CNS) either as brain metastases (BM) or leptomeningeal metastases (LM). Osimertinib is a 3rd generation EGFR TKI effective in T790M mutant NSCLC and characterized by high blood-brain barrier penetration. In this phase II, multicenter prospective single-arm two cohort study, the clinical efficacy of 160mg of osimertinib in T790M mutant BM or LM patients progressed on prior EGFR TKI was evaluated. (NCT0325712)

      Method

      BM only patients were included in the BM cohort (n=40). Patients with cerebrospinal cytology confirmed LM with or without BM were included in the LM cohort (n=40). 3rd generation TKI, including 80mg of osimertinib, was exposed to 18 patients in BM and 16 patients in LM cohort. T790M need to be identified from either tissue, plasma or cerebrospinal fluid. The primary endpoint was overall response rate (ORR) (H1=30%) for BM cohort and overall survival (OS) (H1=5months) for LM cohort, respectively.

      Result

      Median follow-up duration was 7.9 months for BM and 8.3 months for LM cohort. In BM cohort, median progression-free survival (PFS) was 7.3 months (95% confidential interval [CI] 3.6-13.7), and median OS was not reached (NR). Intracranial ORR and disease control rate (DCR) was 40.0% and 77.5%. Extracranial ORR and DCR was 30.0% and 67.5%. In LM cohort, median PFS was 8.9 months (95%CI 5.6-NR) and median OS was 13.2 months (95%CI 8.0-NR). When response of leptomeningeal lesion is separately evaluated, CR rate was 25.0% (n=10) and non-CR/non-PR rate was 65.0% (n=26). Extracranial ORR and DCR was 22.5% and 85.0%. Intracranial median PFS was not reached in both BM and LM cohort. Grade 3 adverse event (AE) was observed in 7 BM and 11 LM patients. Four patients required dose reduction due to AE. Among the patients who previously received 3rd generation TKI, 33.3% (6 out of 18) in BM cohort and 81.2% (13 out of 16) in LM cohort showed an intracranial DCR to 160mg of osimertinib. Extended survival analyses and exploratory outcomes will be presented at the conference.

      Conclusion

      In this study, 160mg of osimertinib demonstrated promising ORR and survival benefit with tolerable safety profile in EGFR T790M positive NSCLC patients with CNS metastasis who progressed on prior EGFR TKI.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-97 - Modified RANO-LM Criteria to Evaluate the Radiological Response of Osimertinib in EGFR T790M Positive NSCLC with Leptomeningeal Metastases (ID 1719)

      09:45 - 18:00  |  Author(s): Hyun Ae Jung

      • Abstract

      Background

      There is no standardized method in tracking the clinical response of leptomeningeal (LM) disease. Based on the recently proposed RANO criteria for LM, we made a further modification which could apply to the clinical trials and real clinical setting. In this study, the feasibility of modified RANO-LM criteria is tested in the exploratory dataset from our prospective clinical trials conducted in EGFR T790M positive non-small cell lung cancer patients with LM (NCT0325712).

      Method

      Based on the previous RANO-LM criteria, up to five leptomeningeal nodules, leptomeningeal enhancement and cranial nerve (CN) enhancement from the baseline was recorded and then changes were scored between -3 to 3 at each post-baseline time point of brain MRI imaging using modified RANO-LM criteria. According to the pre-defined scoring system (figure), all LM lesions were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Presence of hydrocephalus or parenchymal lesion is seperately assessed as non-LM lesion

      abstract_figure.png

      Result

      Response of osimertinib in LM was evaluated in 34 patients. Baseline MRI identified LM enhancement in 67.6% (n=23), CN enhancement in 55.9% (n=19), hydrocephalus in 35.3% (n=12) and parenchymal metastases in 79.4% (n=27) but no nodular lesion (n=0). LM specific overall response rate was 63.9% by showing CR (n=10, 29.4%), PR (n=13, 38.3%), SD (n=8, 23.5%), PD (n=1, 2.9%) in evaluable patients. Eight patients showed treatment resistance by showing disease aggravation in LM lesion (n=2), non-LM lesion (n=5) and both (n=1).

      Conclusion

      Modified RANO-LM criteria seems to be effective in evaluating treatment response and disease progression in patients with LM. Despite the complexity of the scoring system, modified RANO-LM criteria is a feasible method to evaluate LM status which could be applicable both to the clinical trials and to daily clinical practice. Further validation in independent patient cohort will be performed.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-06 - Tumor Microenvironment Landscape in Lung Adenocarcinoma by Single-Cell Sequencing (ID 1227)

      09:45 - 18:00  |  Author(s): Hyun Ae Jung

      • Abstract

      Background

      Lung cancer is the leading cause of cancer cell death in worldwide. Failure of early detection, high recurrence rate and metastasis all contribute to the low survival rate in this detrimental disease. In particular, frequent brain metastasis confers an imperative challenge in the management of lung cancer. Single-cell RNA sequencing provides specific profiling of cell populations at the single-cell level. Interpretation of single-cell transcriptome data for the discovery of therapeutic targets and prognostic biomarkers is an ongoing challenge in precision cancer medicine. Especially, the influence of immune microenvironment in tumor has been accepted as a key factor for determining the therapeutic outcome. Despite the diversity of immune infiltrates in lung adenocarcinoma, single-cell RNA sequencing has not yet been applied for a large-scale tumor and immune profiling.

      Method

      Samples were obtained from the primary tumor, lymph node or brain metastases, and pleural fluids of 44 patients with lung adenocarcinoma. Following lung tumor resection, normal lung tissues from a distal region as well as normal lymph nodes were collected for comparison. We dissociated the whole tissues into single cell suspension and then performed scRNA-seq using droplet-based 10x Genomics Chromiunm platform.

      Result

      After quality filtering, we cataloged a total of 208,506 cells into 9 distinct cell lineages annotated by expression of known marker genes. We identified epithelial cells including cancer cells, stromal cells (fibroblasts and endothelial cells), immune cells (T, NK, B, myeloid, and MAST cells) as common cell types, and oligodendrocytes uniquely from brain metastases. The most abundant immune cell populations at the lung tumor site were T lymphocytes and myeloid cells. Notably, primary tumor and lymph node metastases showed substantial differences in the immune cell composition. These differences reflected the original tissue microenvironment, grossly altered by tumor progression and invasion. Therefore, our lung adenocarcinoma atlas illustrates the dynamic cellular landscape during cancer progression which may reveal progression associated changes for each cellular component in unprecedented scale and manner.

      Conclusion

      These results provide specific tumor microenvironmental patterns in lung adenocarcinoma. Thus, single cell-level transcriptome profiles provide clues to expand therapeutic windows into the combination therapy with immune and anti-cancer reagents.

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    P2.09 - Pathology (ID 174)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.09-07 - Multiple Immunohistochemistry of Non-Small Cell Lung Cancers Reveals Distinct Immune Context (ID 1232)

      10:15 - 18:15  |  Author(s): Hyun Ae Jung

      • Abstract

      Background

      Immune checkpoint blockade improves survival in a subset of patients with non-small cell lung cancer (NSCLC). Though increased tumor infiltrating lymphocytes (TILs) correlate with better outcome in many human cancers, biomarkers that predict response to PD-1 pathway inhibitors remain largely unknown. Therefore, a comprehensive evaluation of the composition and distribution of TILs is necessary to demonstrate their roles.

      Method

      To determine the predictive significance of specific immune cells in the tumor microenvironment, we used multiples IHC. Multiplex IHC is a powerful investigative tool which provides objective quantitative data describing the tumor immune context in both immune subset number and location. To evaluate the immune context broadly we used the OPAL staining panel contains CD8, CD4, CD20, CD68, FOXP3, and panCK.

      Result

      Pathologic tumor specimens from 101 patients with recurred or metastatic NSCLC were analyzed. Tumors exhibited a high degree of heterogeneity in the immune infiltrate and there was no significant difference when immune infiltrates were compared by tumor histology. Furthermore, there were no significant immune cell differences in EGFR mutant tumors or tumors that did not harbor mutations in adenocarcinoma. We observed increased Tregs (CD4+/FOXP3+) in PD-L1-positive tumors as compared with PD-L1-negative tumors. Our results showed that the infiltration levels of most T-cell subpopulations within tumor did not significantly associated with survival. However, high infiltration of B cells significantly correlated with overall survival.

      Conclusion

      Increased infiltration of B cells into tumor regions is an independent predictor of better overall survival in NSCLC. These findings suggest that tumor-infiltrating B cells could act as a clinical factor in anti-PD-1 immunotherapy for NSCLC.

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-57 - Efficacy of 3rd Generation EGFR-TKIs After Failing First or Second Generation EGFR-TKIs in EGFR Mutation-Positive NSCLC (ROOT-EGFR) (ID 1474)

      10:15 - 18:15  |  Presenting Author(s): Hyun Ae Jung

      • Abstract

      Background

      Over the past decade, treatment of EGFR mutation –positive NSCLC has been revolutionized with the development of next generation EGFR TKIs. Four epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib, afatinib and osimertinib, are currently available in Korea. Recent trials have compared the available and emerging EGFR TKIs head to head. The highly anticipated findings of the phase III FLAURA trial showed a nearly doubling of PFS with frontline osimertinib, a third-generation TKI, versus erlotinib or gefitinib.The optimal sequence of EGFR TKIs is still controversial. And many countries 3rd generation EGFR TKI is not readily available. The purpose of this study is to analyze the efficacy in patients who received first-line gefitinib, erlotinib, or afatinib and followed by 3rd generation EGFR-TKIs.

      Method

      This non-interventional observational study through big data analysis will retrospectively collect de-identified patient data from clinical data warehouse (CDW) using a unique algorithm with Standard Query Language (SQL) called ROOT project.

      Result

      Over 10 years, 2,358 patients were diagnosed recurrent or metastatic non-small cell lung cancer and received 1st or 2nd generation EGFR TKIs at Samsung Medical Center. 72.9% (1720/2358) of EGFR mutation-positive NSCLC patients received 1st or 2nd generation EGFR-TKIs as first line palliative chemotherapy. In total population, 30.8% (727/2358) patients received 3rd generation EGFR TKIs. Among them, patients who received 3rd generation EGFR TKI after 1st or 2nd generation EGF TKIs showed better overall survival (45.0 months (95% CI, 41.8-48.2). Among 1720 patients who received 1st or 2nd generation EGFR-TKIs as first line palliative chemotherapy, 313 patients received 3rd generation EGFR-TKIs as 2nd line chemotherapy and 200 patients received as more than 3rd line chemotherapy. However, there was no difference of overall survival between them (44.0 months vs 47.0months, p-value=0.104).

      Conclusion

      This study was meaningful as a study of what can be the best sequence in EGFR-TKI treatment. Updated and detail clinical and exploratory biomarker outcome will be presented at the meeting.

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      P2.14-61 - Acquired Resistance to Entrectinib Associated with Activation of RAS Signaling Pathway in ROS1-Rearranged Non-Small Cell Lung Cancer (ID 1219)

      10:15 - 18:15  |  Author(s): Hyun Ae Jung

      • Abstract

      Background

      ROS1 is a receptor tyrosine kinase (RTK) that is not usually expressed at high levels in normal lung tissue. The wild-type function of ROS1 is unknown, and a natural ligand has not been identified. ROS1 gene rearrangements occur in ~1-2% of patients with NSCLC, and have also been identified in colorectal, gastric and ovarian cancers, glioblastoma and cholangiocarcinoma. ROS1 rearrangements with oncogenic potential have been found to constitutively activate ROS1 signaling, and although it remains unclear exactly how the ROS1 fusion proteins are activated, the PI3K/AKT, MAPK/ERK and JAK/STAT3 pathways are known to be involved. Thus, ROS1-rearranged NSCLCs are ‘addicted’ to ROS1 for cell growth and survival. Knocking down or pharmacologically inhibiting ROS1 has been reported to inhibit growth or induce apoptosis in ROS1-rearranged cell lines. Entrectinib is a pan-tyrosine-kinase inhibitor that targets oncogenic rearrangements in NTRK, ROS1 and ALK. The combined results of two clinical trials demonstrated the efficacy of entrectinib in ROS1-rearranged NSCLC. Because the development of drug resistance is inevitable, it would be helpful to determine the mechanisms of entrectinib resistance in a ROS1-rearranged tumor model so that future therapeutic strategies can be developed.

      Method

      To investigate the effects of entrectinib on ROS1-rearranged NSCLC, we used HCC78 cells harboring an SLC34A2-ROS1 fusion. Entrectinib-resistant HCC78 (HCC78ER) cells were newly established in our laboratory through the exposure of HCC78 cells to gradually increasing concentrations of entrectinib (starting at 100 nM and ending with 5 μM) over 6 months.

      Result

      Here, we characterized the molecular basis of resistance in entrectinib-resistant ROS1-rearranged HCC78 cells (HCC78ER cells). These cells were analyzed by next-generation sequencing and genetic profiling, which revealed the acquisition of KRAS G12C and the amplification of KRAS and FGF3. However, there were no secondary mutations in the ROS1 kinase domain. We also found that sustained ERK activation was involved in entrectinib resistance, and that combined treatment with selumetinib resensitized HCC78ER cells to entrectinib in cell viability and colony formation assays.

      Conclusion

      Our data suggest that activation of the RAS signaling pathway can cause entrectinib resistance in ROS1-rearranged NSCLC, and is unlikely to be overcome by sequential single agent ROS1-targeting strategies against such tumors. Instead, co-targeting ROS1 and MEK may be an effective strategy for overcoming entrectinib resistance in ROS1-rearranged NSCLC.