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Tadaaki Yamada



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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: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-102 - Retrospective Analysis of Immune Checkpoint Inhibitors in Patients with EGFR Mutated Non-Small Cell Lung Cancer in a Japanese Cohort (ID 12068)

      16:45 - 18:00  |  Presenting Author(s): Tadaaki Yamada

      • Abstract

      Background

      EGFR-TKIs led to initial clinical response in most patients with EGFR mutated non-small cell lung cancer (NSCLC). In contrast, little is known the subpopulation of NSCLC patients with EGFR mutations who had clinical outcomes to treat for immune checkpoint inhibitors (ICIs). Therefore, to seek for the eligible cases to treat with ICIs, we retrospectively analyzed the correlations between clinical feature and the efficacy of ICIs in patients with EGFR mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We analyzed a retrospective study of patients with advanced NSCLC harboring with EGFR mutations who were treated with ICIs after the resistance to EGFR-TKIs between February 2016 and April 2018 at five institutions in Japan. The association between clinical outcome and the efficacy or ICIs was investigated.

      4c3880bb027f159e801041b1021e88e8 Result

      We enrolled 27 patients who had EGFR activating mutation. The objective response and disease control rates were higher in patients with uncommon EGFR mutations than in those with common EGFR mutations (57.1% versus 6.3% and 71.4% versus 31.3%, p= 0.003 and p = 0.06, respectively). Patients with uncommon EGFR mutations were associated with a significantly longer median progression-free survival than those with common EGFR mutations (7.0 months versus 1.9 months, p = 0.009).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Uncommon EGFR mutations are associated with better outcomes for the treatment with immunotherapy among EGFR mutated NSCLC in the retrospective analysis. Further research is needed to validate for the clinical biomarkers involved in ICI responders.

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • 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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      P1.13-07 - Epithelial-Mesenchymal Transition Induced the Acquired Resistance to ALK Inhibitor Brigatinib in Lung Cancer Cells Harboring with ALK Fusions (ID 12675)

      16:45 - 18:00  |  Author(s): Tadaaki Yamada

      • Abstract

      Background

      The ALK inhibitors, such as crizotinib and alectinib show a great response to patients with non-small cell lung cancer (NSCLC) harboring ALK fusions. However, the acquired drug resistance is also known as important issues in the treatment with the specific molecular targeted agents, such as EGFR-TKI as well as ALK-TKI. The mechanisms of acquired resistance to ALK-TKI are reported previously, bypass tract signals of EGFR or MET, and Epithelial-mesenchymal transition (EMT). Novel generation ALK inhibitor brigatinib is promising for NSCLC harboring ALK fusions, however, the precise mechanism of the acquired resistance to brigatinib is not fully understood. To elucidate for the novel acquired resistance to brigatinib, we here conducted the cell-based experiments using ALK fusion NSCLC cells.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We established ALK fusion NSCLC cells H3122 (variant 1 E13;A20) and H2228 (variant 3 E6; A20) with the acquired resistance to brigatinib by step-wise methods. ALK inhibitor sensitivity and signal transduction in H3122 and H2228 cells were examined in vitro.

      4c3880bb027f159e801041b1021e88e8 Result

      H3122-brigatinib resistance cell (H3122-BR) and H2228-brigatinib resistance cell (H2228-BR) indicated the cross-resistance to other ALK inhibitors alectinib, crizotinib and lorlatinib. Furthermore, morphological change was observed to spindle shape, and additionally shows decreasing of E-cadherin and increasing of vimentin which are marker of EMT by the western blotting analysis. Moreover, some of these resistant cells cultured with drug-free medium for 4weeks were reversed the sensitivity to ALK-TKIs and cell formation backed to parental cells.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We demonstrated that EMT elicited the acquired resistance to ALK-TKIs under the exposure of brigatinib treatment in ALK fusion NSCLC cells. Further experiments are needed to overcome this drug resistance induced by EMT.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.01-80 - Retrospective Analysis of the Impact of EGFR T790M Mutation Detection by Re-Biopsy in Patients with NSCLC Harboring EGFR Mutations. (ID 12640)

      12:00 - 13:30  |  Author(s): Tadaaki Yamada

      • Abstract

      Background

      EGFR-TKIs show a good response to most of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. However, it ultimately becomes the acquired resistance to EGFR-TKIs after various periods. We currently attempt to detect EGFR-T790M mutation by re-biopsy that induced a half of acquired resistances to them, because the third generation EGFR-TKI osimertinib had an effective response against the refractory tumors with EGFR-T790M mutations. However, the re-biopsy from tumors is relatively invasive and some cases are impossible to perform them. Therefore, it is a critical issue to select the population with EGFR-T790M mutations. In this study, we analyzed the refractory cases to initial EGFR-TKIs with successful re-biopsy samples to disclose these clinical questions.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      78 advanced NSCLC patients with EGFR mutations who had successful re-biopsy samples after the resistance to initial EGFR-TKI treatment are enrolled at five institutions in Japan. We validated for the association between the emergence of EGFR-T790M mutation and their profiles, such as clinical outcomes with EGFR-TKI treatment and EGFR activating mutation status.

      4c3880bb027f159e801041b1021e88e8 Result

      Results

      Of 78 advanced NSCLC patients with EGFR mutations, 39 cases were EGFR-T790M positive and 39 were negative in the re-biopsy samples. Of EGFR-T790M positive patients, 2 cases achieved a complete response (CR), 33 a partial response (PR), and 4 stable desease (SD). In contrast, 1 patients experienced a CR, 19 a PR, 18 SD, and 1 progressive disease (PD) in T790M negative patients. The objective response rate was higher in patients with T790M positive mutations than in those with T790M negative mutations (89.7% versus 51.2%, p< 0.01). There were no difference between each patients in progression free survival and time to failure treated with initial EGFR-TKIs.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Conclusions

      The response to initial EGFR TKI treatment might be one of good predictors for emerging of refractory tumors with EGFR-T790M mutations. Further experiments are needed to identify them.

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