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Wu-Chou Su



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    MA06 - PDL1, TMB and DNA Repair (ID 903)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 AC
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      MA06.01 - The Intrinsic PD-L1 Promotes Cellular Invasiveness Via their PD-1 Receptor in Lung Adenocarcinoma Cells (ID 13356)

      13:30 - 13:35  |  Author(s): Wu-Chou Su

      • Abstract
      • Presentation
      • Slides

      Background

      Lung cancer is the most frequent cause of cancer death. Programmed death 1 (PD-1) in T cells and its ligand PD-L1 in tumor cells play a key role in immune checkpoint therapy and had applied to advanced stage lung cancer. Migration and invasion of tumor cells is a prerequisite for tumor cell metastasis. Since intrinsic PD-1 receptor functions promote tumor growth was reported, we will investigate the interaction between PD-1 and PD-L1 in lung adenocarcinoma cell lines, the impact on chemosensitivity, and clinical outcome.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In vitro experiments, lung adenocarcinoma CL1-5 cells, derived from CL1-0 cells. We prepared PD-L1-overexpression human lung adenocarcinoma cell line, derived from CL1-0 cells (CL1-0-PD1). Migration and invasion ability were assessed by transwell assay; EMT marker and regulator were evaluated by Western blotting. We also observed the morphology of cells. To explore interaction between PD1 and PD-L1, we added anti-PD-1 antibody into CL1-0, CL1-5, and CL1-0-PDL1 cells, and then test migration, invasion and cellular morphology. We also suppressed PD-1 by siRNA to test whether PD-1/PDL-1 interaction contributed to the EMT change. Further, we evaluated cellular proliferation and chemosensitivity by MTT assay and colony formation assay. We will correlate PD-L1 expression in lung cancer cells with clinical outcome by IHC stain clinically.

      4c3880bb027f159e801041b1021e88e8 Result

      In CL1-5 cells, derived from CL1-0 cells, with high PD-L1 expression possessed higher cellular migration ability than the parental CL1-0 cells with less PD-L1 expression. CL1-0 cells with PD-L1 overexpression had more expression of EMT (epithelial mesenchymal transition) regulator and mesenchymal marker. We also observed that CL1-5 and CL1-0-PDL1, which had more PD-L1 expression, are shaped like spindles; while CL1-0 cells are more rounded. Therefore, PD-L1 up-regulated cell migration and invasiveness in human lung adenocarcinoma cells and promotes EMT.

      After adding anti-PD1 antibody in CL1-5, CL1-0, and CL1-0-PDL1 cells, migration and invasion ability decreased. These result indicated anti-PD-1 antibody block the link between PD-1 and PD-L1 in cancer cells. The phenomenon was confirmed by PD-1 siRNA. Therefore, PD-1/PD-L1 axis regulated cancer cells migration and invasiveness. PD-L1 expression also decreased cellular proliferation and had little influence on chemsensitivity. Finally, we found that higher PD-L1 expression was correlated with lymph node metastasis in clinical specimen.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lung adenocarcinoma cells with higher PD-L1 expression promote cell migration, invasiveness, EMT, and little chemoresistance. PD-L1 expression lowers proliferation rate. PD-1 and PD-L1 interaction on lung adenocarcinoma cells contribute cellular migration and invasiveness.

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      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-60 - Preventing and Treating Brain Metastases with Three First-Line EGFR-TKI in Patients with EGFR Mutation Advanced NSCLC (ID 12010)

      16:45 - 18:00  |  Author(s): Wu-Chou Su

      • Abstract
      • Slides

      Background

      Brain metastases (BM) are common in advanced non-small cell lung cancer (NSCLC), and the prognosis is poor with few therapeutic options. This retrospective study evaluated the efficacy of three epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in preventing and treating BM in patients with EGFR mutation-positive advanced NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All patients with EGFR mutation-positive advanced NSCLC who visited a tertiary referral center from December 1, 2013, to November 30, 2017, were analyzed retrospectively. These patients received gefitinib, erlotinib, or afatinib until disease progression, death, or intolerable adverse events. The cumulative incidence of subsequent BM and the progression-free survival (PFS) and overall survival (OS) of both the BM patients and non-BM patients were estimated by the Kaplan-Meier method and compared using the log-rank test. We performed Cox proportional hazards regression for the predictors of subsequent BM and determinants of PFS and OS.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 306 patients with newly diagnosed or recurrent NSCLC were enrolled. Among these patients, 116, 75, and 115 received first-line gefitinib, erlotinib, and afatinib, respectively. The patients who received afatinib had a better PFS (12.7 versus 9.8 months, p=0.001) and OS (39.1 versus 22.0 months, p=0.035) than those who received gefitinib. The cumulative incidences of subsequent BM were similar among the patients who received different TKIs (p=0.80). Patients with initial BM were associated with a shorter PFS (p < 0.001) and OS (p=0.015) than those without BM. Among the initial BM patients, there were no differences in median PFS (p=0.34) and median OS (p=0.46) in the three EGFR-TKI groups.

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      8eea62084ca7e541d918e823422bd82e Conclusion

      Our data suggested afatinib provided significant benefits in terms of PFS and OS as well as preventing subsequent BM compared to gefitinib, in addition to providing the same effectiveness in treating BM as gefitinib

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-98 - A Phase IIIb Trial of Afatinib in EGFRm+ NSCLC: Analyses of Outcomes in Patients with Brain Metastases or Dose Reductions (ID 12906)

      16:45 - 18:00  |  Author(s): Wu-Chou Su

      • Abstract

      Background

      We previously reported interim results of a large (n=479) open-label, single-arm Phase IIIb study of afatinib in EGFR TKI-naïve patients with EGFRm+ NSCLC, in a setting similar to ‘real-world’ practice (Wu et al, WCLC, 2017). In this broad population of Asian patients, the tolerability profile of afatinib was predictable and manageable. Adverse events (AEs) were consistent with the LUX-Lung 3, 6 and 7 trials; 3.8% of patients discontinued due to drug-related AEs. Progression-free survival (PFS) and time to symptomatic progression (TTSP) was encouraging, in patients with both common and uncommon EGFR mutations. TTSP data suggested effective treatment beyond progression. Here, we assess the impact of baseline brain metastases and use of dose reductions on efficacy outcomes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with locally advanced/metastatic EGFRm+ NSCLC were recruited in China, Hong Kong, India, Singapore and Taiwan. Afatinib 40mg/day was given until disease progression (investigator-assessed) or lack of tolerability. Treatment-related AEs could be managed by protocol-specified tolerability-guided dose adjustment.

      4c3880bb027f159e801041b1021e88e8 Result

      At data cut-off (13 Feb 2017), patient characteristics were as follows: median age, 59.0 years; female, 52.4%; EGFR mutations: Del19+/-L858R+/-uncommon, 86.0%; uncommon only, 14.0%; ECOG PS0, 19.8%; PS1, 78.1%. Prior chemotherapy lines: 0, 59.7%; 1, 30.1%; ≥2, 10.2%.

      Overall, dose reductions from 40mg/day to 30mg/day occurred in 119 patients (25%). Incidences of the most frequently reported AEs before and after dose reduction were (any grade): diarrhea, 96/51%; rash/acne, 69/58%; stomatitis, 65/42%; (≥grade 3) diarrhea, 27/4%; rash/acne, 24/11%; stomatitis, 11/5%. A total of 96 patients had a dose reduction during the first six months; median PFS in this subgroup was 14.1 months (95% CI: 10.0–19.3) versus 11.33 (10.7–13.6) months in those who remained on the starting dose (n=383); HR=1.37 (1.01–1.85), p=0.041. Median TTSP was 17.7 (13.5–23.7) and 14.7 (12.7–17.0) months, respectively; HR=1.26 (0.92–1.72), p=0.15.

      Among 92 patients (19.2%) with brain metastases at baseline, median PFS was 10.9 (8.3–14.3) months, versus 12.4 (10.8–13.9) months in those without metastases (n=387); HR=1.23 (0.91–1.65), p=0.18. Median TTSP was 14.8 (12.7–20.7) and 15.4 (12.9–18.0) months, respectively; HR=1.0 (0.71–1.40), p=1.0.

      8eea62084ca7e541d918e823422bd82e Conclusion

      These findings demonstrate that tolerability-guided dose adjustment of afatinib is an effective measure to reduce treatment-related AEs, while maintaining therapeutic efficacy. TTSP was similar between patients with and without brain metastasis. This is additional evidence for the efficacy of afatinib in patients with brain metastases.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.11 - Screening and Early Detection (Not CME Accredited Session) (ID 943)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.11-13 - Noninvasive Detection of Early Stage NSCLC EGFR Mutations Using Electric Field Induced Release and Measurement (EFIRM) (ID 11776)

      16:45 - 18:00  |  Author(s): Wu-Chou Su

      • Abstract
      • Slides

      Background

      The ability of liquid biopsy to detect circulating tumor mutations has proved especially valuable in the treatment of patients with NSCLC since well characterized variants inform small molecule chemotherapeutic options.

      EFIRM is a signal amplification technology that allows direct detection of mutations in native plasma and saliva without amplification or sequencing. Previously published work demonstrated a near perfect correlation between biopsy and EFIRM results for the Exon19 del and p.L858R mutations in EGFR in late stage NSCLC patients. In this study we investigated the performance of EFIRM in patients early stage (I and II) NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Plasma samples were collected from 33 healthy controls with biopsy proven benign lung masses and 21 stage I and II NSLC patients with biopsy proven EGFR mutations The samples were immediately centrifuged and frozen. The samples were then blinded and sent for EFIRM analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 12 biopsies positive for p.L858R (11 stage 1 and 1 stage II) and 9 positive for Exon 19 del (7 stage 1A, and 2 stage II). Using statistically derived cut-offs to optimize sensitivity and specificity, there were 2 false positives (both for p.L858R) in the controls yielding an overall specificity of 91% for the 2 SNP Mutation assay. The sensitivity was 92% for the p.L858R with only one negative in 12 samples in a patient with stage 1 and 77% for Exon 19 del with 2 negatives in 9 samples in a single patient each for stage 1 and 2.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The preponderance of patients in this study had stage I NSCLC. The sensitivity of 94% and 77% respectively for the 2 most common mutations is remarkable for patients with Stage 1 lung cancer and a correspondingly low tumor burden and more importantly at a potentially curable stage. We are in the process of improving the technical performance of this assay and adding additional variants to the panel in order to increase clinical utility. These data are promising for the potential use of the EFIRM platform for the purposes of drug selection, disease recurrence, follow-up of indeterminate lung nodules from spiral CT screening programs, and / or population screening.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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