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Terufumi Kato



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    EP1.01 - Advanced NSCLC (ID 150)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.01-72 - Treatment Outcome of 2nd Generation EGFR-TKI for Non-Small Cell Lung Cancer (Now Available) (ID 1988)

      08:00 - 18:00  |  Author(s): Terufumi Kato

      • Abstract
      • Slides

      Background

      Efficacy of EGFR-TKI has been demonstrated in 1st line treatment for EGFR mutation positive NSCLC. Afatinib, 2nd generation EGFR-TKI inhibits HER2 (ErbB2) or ErbB4 in addition to the EGFR (ErbB1), is expected more effective compared to the 1st generation EGFR-TKI. In this study, we investigated retrospectively on the treatment outcome of the cases that received 2nd generation EGFR-TKI treatment at our institution.

      Method

      The subjects were 70 patients treated with a 2nd generation EGFR-TKI afatinib for the period from May 2014 to April 2018. Age, gender, smoking history, performance status (ECOG), EGFR mutation type, starting dose, dose reduction during treatment period, objective response, presence of brain metastasis, EGFR-TKI treatment line and T790M mutation result were retrospectively analyzed the association with the time to treatment failure and survival.

      Result

      Among the 70 patients, male 28 cases and female 42 cases, and 42 never smoker included. Median age was 65 years old (43-88 years old). EGFR mutation type included exon 19 deletion 42 cases, exon 21 L858R 13 cases, uncommon mutation 13 cases and compound mutation 2 cases. 18 cases were administered with 40mg initial dose, 28 cases were 30mg and 24 cases were 20mg. 68 cases were good performance status (0 or 1), and 33 (47%) cases had brain metastasis. Dose reduction were performed in 43 (61%) cases, and partial response were observed in 34 (49%) cases. 36 (51%) cases were no pretreatment with EGFR-TKI (afatinib as first EGFR-TKI). Of the 70 cases, 33 (47%) cases were performed re-biopsy, and 15 cases of those were proved T790M acquired resistant mutation.

      Conclusion

      Good performance status, dose reduction, good objective response, no brain metastasis, early EGFR-TKI treatment line and T790M mutation positivity were significantly associated with prolongation of the time to treatment failure, but no significant characteristics were associated with prolongation of the survival.

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    OA07 - Precision Medicine Involves Biology and Patients (ID 132)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      OA07.03 - Clinical Outcome of Non-Small Cell Lung Cancer with EGFR/HER2 Exon 20 Insertions Identified in the LC-SCRUM-Japan (Now Available) (ID 629)

      11:00 - 12:30  |  Author(s): Terufumi Kato

      • Abstract
      • Presentation
      • Slides

      Background

      In-frame insertions in exon 20 (Ex20ins) of EGFR/HER2 occur in 2-5 % of non-small cell lung cancer (NSCLC). There is no approved targeted therapy for patients with these mutations. Historical control data would be valuable for the development of novel targeted therapies for these rare cancers.

      Method

      A nationwide genome screening project in Japan (LC-SCRUM-Japan) has been established for the development of molecular-targeted therapies for lung cancers. In this project, 161 cancer-related genes have been analyzed by a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay. The therapeutic efficacy and survival of the patients with non-squamous (non-sq) NSCLC harboring EGFR/HER2 Ex20ins were evaluated using a large-scale clinico-genomic database in the LC-SCRUM-Japan.

      Result

      A total of 3441 advanced non-sq NSCLC patients were successfully analyzed from 2015 to 2018. EGFR Ex20ins were detected in 73 patients (2%; M766_A767insASV/A767_S768insSVD/H773_V774insH/D770_N771insNPH/N771_P772insPH/others=22/17/5/4/4/21) and HER2 Ex20ins were detected in 128 patients (4%; A775_G776insYVMA/G776delinsVC/P780_Y781insGSP/others=95/16/10/7). The median age of the patients was 62 (range, 33-90) years. Eighty-one patients (40%) were male and 114 (57%) were never smoker. Two-hundred patients (99%) were diagnosed as adenocarcinoma and 1 as adenosquamous-cell carcinoma. Based on our database, the median overall survivals in patients with EGFR Ex20ins were 22.4 (95%CI, 15.3-36.8) months, and those with HER2 Ex20ins were 18.8 (13.6-30.3) months. In the patients with EGFR/HER2 Ex20ins, the objective response rate (ORR) and median progression-free survivals (mPFS) of 1st-line platinum-containing chemotherapies were 32% and 6.0 (5.7-7.0) months, respectively. The ORR and mPFS of docetaxel with or without ramucirumab were 26% and 5.1 (3.8-5.9) months, respectively. The ORR and mPFS of PD-1 inhibitor were 0% and 2.0 (1.6-2.6) months, respectively. No significant difference in the therapeutic efficacy of these drugs was observed between the patients with EGFR Ex20ins and HER2 Ex20ins. In 19 patients with EGFR Ex20ins treated with 1st/2nd generation EGFR-TKIs, the ORR was 5% (a M766_A767insASV-positive tumor responded to afatinib) and the mPFS was 2.1 (1.3-4.2) months.

      Conclusion

      The patients with EGFR/HER2 Ex20ins-positive NSCLC showed poor responses to PD-1 inhibitors and 1st/2nd generation EGFR-TKIs. These historical data are highly informative in evaluating the efficacy of novel targeted therapies for EGFR/HER2 Ex20ins-positive NSCLC.

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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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      P1.04-14 - Early Changes in Plasma CXCL2 and MMP2 Levels Predicts the Response to Anti-PD-1 Therapy in Non-Small-Cell Lung Cancer (ID 1675)

      09:45 - 18:00  |  Author(s): Terufumi Kato

      • Abstract

      Background

      Previously we reported that changes in the plasma levels of CXCL2 and MMP2, measured by a bead-based multiplex assay: Bio-Plex 200 system, were significantly associated with the clinical outcomes of anti-PD-1 therapy (Matsuo, et al. IJC. 2018). Here we attempted to validate CXCL2 and MMP2, measured by ELISA, as a marker of the effectiveness of anti-PD-1 therapy in expanded patient cohort.

      Method

      Peripheral blood samples were taken from 97 patients with non-small cell lung cancer before nivolumab or pembrolizumab treatment and after 4-10 weeks from the patients who continued these drugs. The levels of CXCL2 and MMP2 were examined before and after anti-PD-1 therapy. We employed Cox regression analysis for CXCL2 and MMP2 as a single explanatory carriable. In comparing the fitness of CXCL2 and MMP2 Cox models, discrimination was assessed by the Harrell’s C-statistic for survival data. Bootstrap methods with 10000 resamplings were used to assess the stability of the regression analysis predictors. The optimal cutoff point was determined as the point at which the Youden index was maximized by ROC curve. Survival curves were generated using the Kaplan–Meier method and comparisons made using the log-rank test.

      Result

      The changes in the plasma levels of CXCL2 after treatment were significantly correlated with PFS (HR 1.003, 95%CI: 1-1.005, P=0.026) and OS (HR 1.004, 95%CI: 1.001-1.007, P=0.003). The C-statistic of the CXCL2 model for PFS and OS were 0.652 (95% CI: 0.437-0.727) and 0.626 (95% CI: 0.528-0.722), respectively. The decreasing revels of CXCL2 tended to be related to better DCR (P=0.134). The changes in the plasma levels of CXCL2 < 29.1 pg/ml was associated with better PFS (HR 2.872, 95%CI: 1.785-4.618, P<0.001) and OS (HR 2.800, 95%CI: 1.633-4.801, P<0.001). The changes in the plasma levels of MMP2 after treatment were also significantly correlated with PFS (HR 0.998, 95%CI: 0.996-0.999, P=0.003) and OS (HR 0.998, 95%CI: 0.996-0.999, P=0.001). The C-statistic of the MMP2 model for PFS and OS were 0.599 (95% CI: 0.515-0.673) and 0.614 (95% CI: 0.523-0.703). The increasing revels of MMP2 was significantly related to better DCR (P=0.020). The changes in the plasma levels of MMP2 > 0.847 ng/ml was associated with better PFS (HR 0.614, 95%CI: 0.388-0.971, P=0.037) and OS (HR 0.501, 95%CI: 0.295-0.852, P=0.011).

      Conclusion

      The early change of CXCL2 and MMP2 were significantly associated with the clinical outcomes of anti-PD-1 therapy. Since these factors in plasma can be easily measured by minimally invasive method, they could be clinically applicable as biomarkers for predicting the clinical benefit of anti-PD-1 therapy for NSCLC patients.

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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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      P2.14-55 - Real-World Safety and Efficacy Data of Osimertinib in Patients from Japan with EGFR T790M-Positive NSCLC (ID 1601)

      10:15 - 18:15  |  Author(s): Terufumi Kato

      • Abstract
      • Slides

      Background

      Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was approved in Japan on 28 March 2016 as second- or later-line treatment for patients with EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) who have progressed on EGFR-TKIs. Post-marketing activities included the Japan-local All-patient Clinical Experience Investigation, reporting Japanese real-world safety and efficacy of osimertinib in the approved indication.

      Method

      Overall, 3629 patients investigated at 718 hospitals between 28 March 2016 and 31 August 2018 were included. Adverse events were assessed by attending physicians to determine whether they were possibly causally-related to osimertinib. Osimertinib antitumour activity was evaluated by attending physicians using RECIST version 1.1. Progression-free survival (PFS) and overall survival (OS) were also analysed. The planned observation period was 12 months.

      Result

      The median observation period for patients in the safety analysis set (n=3578) was 343 days (range: 1–764). Adverse drug reactions occurred in 58.1% (2079/3578) of patients. Adverse drug reactions (as per Japanese Prescribing Information) of interstitial lung disease, prolonged QT interval, liver disorder, and haematotoxicity were reported in 6.8% (245/3578) (Gr≥3, 2.9% [104/3578]), 1.3% (45/3578) (Gr≥3, 0.1% [5/3578]), 5.9% (212/3578) (Gr≥3, 1.0% [35/3578]), and 11.4% (409/3578) (Gr≥3, 2.9% [104/3578]) of patients, respectively. The objective response rate and disease control rates for patients in the efficacy analysis set (n=3563) were 69.9% (2492/3563; 95% confidence interval [CI] 68.4, 71.4) and 86.7% (3090/3563; 95% CI 85.6, 87.8). PFS rates at 6 months and 12 months were 77.4% (95% CI 75.9, 78.9) and 53.2% (95% CI 51.3, 55.1). OS rates at 6 months and 12 months were 88.3% (95% CI 87.2, 89.4) and 75.4% (95% CI 73.8, 77.0). Selected subgroup analyses of efficacy are presented in Table 1.

      wclc 2019 japn pms table.png

      Conclusion

      These data support the currently established benefit–risk assessment of osimertinib in patients with EGFR T790M positive NSCLC.

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    PC05 - Immune Chekpoint Inhibitors in Real World - How Do We Treat NSCLC ''Special Populations'' (ID 87)

    • Event: WCLC 2019
    • Type: Pro-Con Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      PC05.01 - ICIs for Patients with Interstitial Pneumonia (Now Available) (ID 3574)

      14:30 - 16:00  |  Presenting Author(s): Terufumi Kato

      • Abstract
      • Presentation
      • Slides

      Abstract

      Interstitial pneumonia (IP) or pulmonary fibrosis (PF) is one of the most common and poor prognostic comorbidities with lung cancer, and also known as a risk factor of treatment related pneumonitis. Around 10% of patients are diagnosed concomitant IP/PF at the time of cancer diagnosis.

      The prognosis of lung cancer patients with IP/PF has been reported to be poor, because 5-20% of those receiving chemotherapy experienced exacerbation of IP/PF, and some of them are mortal. Median overall survival time of these patients with stage IV non-small cell lung cancer is around 10 months, which is 2 months shorter than patients without IP/PF. In spite of risk of acute exacerbation, chemotherapy including platinum doublet or monotherapy are considered as the standard treatment for the patient with IP/PF because of a certain level of efficacy.

      Not only chemotherapy, other types of cancer treatment including radiotherapy, surgical resection, and targeted drug also induce acute exacerbation of pre-existing IP/PF occasionally.

      Targeted small molecules including EGFR-TKIs are reported to have higher risk of acute exacerbation of pre-existing IP/PF, and some surveillance reports that existence of IP/PF is a most significant risk factor related to emergence of treatment related pneumonitis.

      Immuno-checkpoint inhibitors (ICI) now play an important role in lung cancer treatment, and as immune related adverse event, immune mediated pneumonitis is considered that should be paid most attention because of its high frequency and potential lethality. Regarding to ICI, relation between pre-existing IP/PF and treatment related pneumonitis is not clear, so far.

      Because of relationship to smoking history, higher level of microsatellite instability (MSI), and tumor mutation burden (TMB), these are associated with favorable efficacy, ICI also may have some role in treatment strategy for the lung cancer patients comorbid with IP/PF.

      A phase II trial of nivolumab for pretreated NSCLC patients with IP/PF, in 18 pretreated NSCLC patients with mild idiopathic IP, showed 36% of response rate and a 56% of 6-months progression-free survival rate in mild idiopathic IP. Two grade 2 pneumonitis were observed, and both are improved by corticosteroid treatment.

      In this session I will try to review ICI treatment for patients with IP/PF and also discuss about their clinical adaptation for clinical practice.

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