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Takamasa Koga



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    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA09.10 - Comprehensive Analysis of Secondary Mutation as Resistance Mechanism to Seven MET-TKIs for MET Exon 14 Skipping in Vitro (Now Available) (ID 117)

      15:15 - 16:45  |  Author(s): Takamasa Koga

      • Abstract
      • Presentation
      • Slides

      Background

      MET exon 14 skipping mutation have been attracting attentions of thoracic oncologists as a new target of therapy for lung cancer. The efficacy of MET-TKI has been reported, while these tumors, almost always acquire resistance, as in the case of other oncogene-addicted lung cancers. However, its resistance mechanisms are not fully understood.

      Method

      MET exon14 skipping mutation was introduced to Ba/F3 cell retrovirally. Using N-ethyl-N-nitrosourea mutagenesis, we derived resistant clones to seven MET-TKIs and searched for secondary MET mutations. We evaluated their sensitivities to following different TKIs. Type Ia, crizotinib; Type Ib, capmatinib, tepotinib and savolitinib; Type II, cabozantinib, merestinib and glesatinib.

      Result

      We sequenced 201 resistant clones and could obtain 80 clones which had secondary mutations in the MET tyrosine kinase domain. A total of 26 different missense mutations occurring at 12 codons were identified. Of them, D1228 and Y1230 in the activation loop were common sites for type I TKIs that bind to active kinase form (DFG-in), while L1195 and F1200 were those for type II TKIs that bind to inactive form (DFG-out). In general, resistant mutations against type I were sensitive to type II, and vice versa.

      figure.png

      Conclusion

      We identified mutation sites specific for TKI types as resistance mechanisms and complementary activities between type I and type II inhibitors against those mutations. These finding should provide relevant clinical implication for treating patients with lung cancer harboring MET exon 14 skipping.

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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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      P1.04-55 - Comparison of PD-L1 Expression Status Between Pure-Solid Versus Part-Solid Tumors in Lung Adenocarcinomas (ID 169)

      09:45 - 18:00  |  Author(s): Takamasa Koga

      • Abstract

      Background

      Recent studies have reported clinicopathological and prognostic differences between lung adenocarcinomas with ground-glass opacity (GGO) versus those without GGO (pure-solid tumors). However, it is unknow if the expression status of PD-L1 protein differs between these two groups.

      Method

      One-hundred twenty-four stage IA – IB lung adenocarcinoma patients who received pulmonary resection between 2007 – 2009 were included in this study. PD-L1 staining was performed in our previous study using E1L3N antibody. PD-L1 status was classified as positive if 1% or more tumor cells showed membrane staining; and was classified as strong positive if 50% or more tumor cells did so.

      Result

      Among 124 lung adenocarcinoma patients, 45 had lung adenocarcinomas with GGO and 79 had pure-solid lung adenocarcinomas. We observed no significant differences between these two groups in terms of clinical factors (gender, age, and smoking status). However, the rates of PD-L1 positive tumors (4% vs 25%, p < 0.01) and PD-L1 strong positive tumors (2% vs 16%, p = 0.02) were significantly lower in lung adenocarcinomas with GGO. In multivariate analyses, these correlations between the presence / absence of GGO and PD-L1 expression status were still evident as shown in Table 1.table 1..png

      Conclusion

      Lung adenocarcinomas with GGO were less frequent to express PD-L1 compared to pure-solid lung adenocarcinomas.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-37 - Lower Risk of Hypercoagulability in Non-Small Cell Lung Cancer Patients with EGFR Mutations (ID 1602)

      10:15 - 18:15  |  Author(s): Takamasa Koga

      • Abstract

      Background

      Hypercoagulability is sometimes observed in cancer patients, including non-small cell lung cancer (NSCLC) patients. Plasma levels of fibrinogen or D-dimer are used as markers for hypercoagulability, and several previous studies have reported that upregulation of these markers are poor prognostic factors in NSCLCs. On the other hand, recent studies have highlighted clinical differences between NSCLCs with EGFR mutation and those without. However, there is no data about the difference in hypercoagulability between NSCLCs with EGFR mutation and those without.

      Method

      Between January 2007 to December 2016, 270 surgically resected NSCLC patients received EGFR mutation testing and were included in this study. Plasma fibrinogen and D-dimer levels were examined as one of pre-surgical examinations in all patients. We analyzed the correlation between plasma fibrinogen / D-dimer levels and EGFR mutation status.

      Result

      Among 270 patients in our cohort, 123 patients had EGFR mutation and 147 patients were wild type (WT) for the EGFR. In our cohort, plasma fibrinogen level was upregulated in 39 patients, while plasma D-dimer level was upregulated in 75 patients. Plasma fibrinogen was upregulated in 9 patients (7%) and in 30 patients (20%) in EGFR mutation group and in WT EGFR group, respectively (p = 0.0017). Plasma D-dimer was upregulated in 27 patients (22%) and in 48 patients (33%) in EGFR mutation group and in WT EGFR group, respectively (p = 0.049). These correlations were still significant after the adjustment with clinical factors including smoking status, age, and histology. In multivariate analysis, odds ratio and 95% CI in EGFR mutation group for upregulated plasma fibrinogen were 0.40 and 0.17 – 0.94, respectively (p = 0.037). On the other hand, odds ratio and 95% CI in EGFR mutation group for upregulated plasma D-dimer were 0.48 and 0.26 – 0.90, respectively (p = 0.022).

      Conclusion

      Plasma levels of fibrinogen and D-dimer were significantly lower in NSCLCs with EGFR mutation.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-20 - Potent in Vitro Activity of Tarloxotinib for HER2 Exon 20 Mutations in Lung Cancer and Mechanism of Acquired Resistance (ID 2093)

      10:15 - 18:15  |  Presenting Author(s): Takamasa Koga

      • Abstract

      Background

      Oncogenic HER2 (ERBB2) mutations are present in 2-3% of lung adenocarcinoma. No targeted therapy is currently approved for HER2-mutated lung cancers, and clinical trials using novel irreversible pan-HER inhibitors are underway. However, all of these irreversible pan-HER inhibitors are also active against wild-type (WT) EGFR, resulting in dose limiting toxicities. Tarloxotinib is a novel clinical-stage prodrug that releases a potent, irreversible pan-HER inhibitor (tarloxotinib-E) selectively in pathologically hypoxic regions of tumors. In this study, we evaluated tarloxotinib-E activity against various HER2 exon20 insertion mutations and explored the resistance mechanisms to tarloxotinib-E.

      Method

      We introduced WT HER2 or HER2 activating mutations, including A775_G776insYVMA, G776delinsVC, and P780_Y781insGSP into Ba/F3 cells by retroviral transfection. Growth inhibitory assays were performed in these Ba/F3 cells and in H1781 cells (G776delinsVC). Tarloxotinib-E resistant clones were established by exposing these Ba/F3 cells to 200nM of tarloxotinib-E after treatment with N-ethyl-N-nitrosourea. Acquired resistant cells to tarloxotinib-E were also developed from H1781 cells via chronic exposure to increasing concentrations of tarloxotinib-E. HER2 secondary mutations were detected by direct sequencing.

      Result

      Tarloxotinib-E displayed potent activity against WT and mutant HER2 Ba/F3 cells and H1781 cells. Furthermore, the IC50 of tarloxotinib (prodrug) for wild-type HER2 was > 100 times higher than that of tarloxotinib-E (active drug). So far, we established 12 tarloxotinib-E resistant clones from Ba/F3 models (6 with A775_G776insYVMA and 6 with G776delinsVC), all of which harbored C805S secondary mutation (corresponding to C797S of the EGFR).tarlo ic50.jpg

      Conclusion

      Tarloxotinib-E exhibited potent activity for all HER2 exon 20 mutations. We identified secondary HER2 C805S mutation as a common mechanism of acquired resistance, consistent with the covalent binding mode of tarloxotinib via this residue. Additional resistant clones are currently being evaluated.

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-16 - T790M or C797S Confers Acquired Resistance to Tarloxotinib and Poziotinib in EGFR Exon 20 Insertion-Driven Lung Cancer Models in Vitro (ID 1694)

      10:15 - 18:15  |  Author(s): Takamasa Koga

      • Abstract

      Background

      Lung cancers with EGFR exon 20 insertion mutations are refractory to current available tyrosine kinase inhibitors. Recent evidence suggests the therapeutic potential of the novel hypoxia-activated prodrug, tarloxotinib, a potent pan-HER inhibitor, or the repurposed 3rd generation inhibitor, poziotinib in these tumors. However, it is assumed that acquired resistance to these agents will be inevitable. In this study, we explored secondary mutations that may confer resistance to these agents using Ba/F3 models.

      Method

      Ba/F3 cells with various EGFR exon 20 mutations (A763insFQEA, V769insASV, D770insSVD, and H773insNPH) were generated by retroviral transfection. TKI resistant clones were established by exposure of parental cells to either tarloxotinib-E (active form of tarloxotinib) or poziotinib after treatment with N-ethyl-N-nitrosourea (ENU) mutagenesis agent. EGFR secondary mutations were detected by direct sequencing.

      Result

      ENU mutagenesis resulted in 62 tarloxotinib-E-resistant clones and 56 poziotinib-resistant clones using 200 nM of either drug. Ba/F3 cells with A763insFQEA were highly sensitive to these agents and only 1 tarloxotinib-resistant clone (C797S) was obtained. In Ba/F3 cells with V769insASV, all 14 tarloxotinib-resistant clones and 15 poziotinib-resistant clones developed T790M mutation. In Ba/F3 cells with D770insSVD cells, all 24 tarloxotinib-resistant clones and 20 poziotinib-resistant clones developed C797S mutation. In Ba/F3 cells with H773insNPH cells, 22 of 23 tarloxotinib-resistant clones and 21 of 22 poziotinib-resistant clones developed T790M mutation, while the rest of the clones harbored C797S mutation.

      Conclusion

      These results suggested that either T790M or C797S could cause acquired resistance to tarloxotinib and poziotinib in lung cancer models with EGFR exon 20 insertion mutations. Interestingly, the type of resistance mutation is likely to be dependent on the context of the original EGFR exon 20 insertion mutation.