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Hitomi Umeguchi



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    EP1.14 - Targeted Therapy (ID 204)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.14-10 - Investigation of Mechanisms of Acquired Resistance to Afatinib with Plasma DNA in Non-Small Cell Lung Cancer Patients (Now Available) (ID 1535)

      08:00 - 18:00  |  Author(s): Hitomi Umeguchi

      • Abstract
      • Slides

      Background

      Afatinib, the 2nd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been evidenced better efficacy compared to 1st generation EGFR-TKI by phase III studies, but the problem is to acquire resistance approximately one year after treatment. The detail mechanisms of acquired resistance to afatinib has not clarified, although T790M was also detected at time to acquired resistance. Recently, the 3rd generation EGFR-TKI, osimertinib has been approved as the first line setting. As for the mechanisms of acquired resistance to osimertinib as 1st line, various kinds of pathway beside EGFR contributed, suggesting difficulty to select next treatment strategy after osimertinib. Considering how to use 1st, 2nd and 3rd approximately, it has been reported that longer PFS was shown among the patients who were treated with osimertinib following afatinib, compared to 1st generation EGFR-TKI. Based on these evidences, we hypothesize that mechanisms of acquired resistance to afatinib may be less genetic alterations compared to osimertinib, and these alterations could be limited to EGFR pathway, resulting in EGFR-TKI sequencing, from afatinib to osimertinib showed better prognosis.

      Because the concept of tumor evolution showed that the number and kind of genetic alterations were increased after treatment modifications, comprehensive assay system is indispensable for evaluation of acquired resistance. Moreover, non-invasive assay system such as liquid biopsy is needed since distant metastases are often observed in advanced lung cancer patients. Guardant360™, a high sensitive digital sequencing system with plasma DNA has been developed by Guardant Health, enable to detection of SNV of 73 genes, in/del of 23 genes, amplification of 18 genes, and fusions of 6 genes. The assay system enables us to detect 0.03% allele fraction.

      The purpose of this study is to clarify mechanism of acquired resistance to afatinib with liquid biopsy to determine best EGFR-TKI sequencing.

      Method

      Study Design

      Prospective observational study

      Primary objective

      To determine mechanisms of acquired resistance to afatinib with plasma DNA

      Target sample size

      40.

      We are planning to compare with the results of patients who acquired resistance to osimertinib with liquid biopsy performed in FLAURA.

      So far, 29 patients acquired resistance to afatinib, and we collected these blood samples.

      Sample preparation

      Collection of samples

      1. before afatinib treatment and at PD to afatnib

      2. collection of 5ml blood with sodium citrate collection tube

      Genomic examinations

      NGS is performed in Guardant Health.

      Result

      This study had finished enrollment and under analysis now.

      Conclusion

      Comprehensive analysis are needed to clarify the mechanisms of acquired resistance to afatinib to facilitate consideration of the best sequence of 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
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-47 - Prospective Study for Usefulness of Plasma DNA on Prediction of Third Generation EGFR Tyrosine Kinase Inhibitors (S-PLAT Study) (Now Available) (ID 1112)

      09:45 - 18:00  |  Author(s): Hitomi Umeguchi

      • Abstract
      • Slides

      Background

      The AURA and FLAURA studies have shown that EGFR T790M mutation detected in cfDNA is correlated with efficacy of osimertinib as measured via overall response rate (ORR), and progression-free survival (PFS). However, the following clinical-related questions have been raised: Can other different assay systems confirm the results mentioned above? Does T790M level affect osimertinib treatment efficacy? Do mutations at loci other than EGFR influence treatment efficacy?

      Method

      This is a prospective observational study, joining 27 Japanese hospitals. Plasma samples from patients with non-small cell lung cancer (NSCLC) who acquired resistance to EGFR-TKI (gefitinib, erlotinib, afatinib) were collected between Feb 2017 and Jan 2019. We tested T790M by MBP-QP method which has been newly developed using cfDNA and investigated the concordance with the result by cobas EGFR mutation Test v.2 (tissue and/or plasma) which is commercially available. We also checked the allele frequency (AF) of T790M in cfDNA by ddPCR and the mutational status of cancer related actionable genes by cfDNA specific NGS (Guardant360). The major objectives were ORR, disease control rate (DCR) to osimertinib and PFS in patients with T790M positive by MBP-QP method.

      Result

      Among 145 NSCLC patients who acquired resistance to 1st or 2nd EGFR-TKI, T790M was detected in 57 patients by cobas (tissue and/or plasma), and these patients received osimertinib (80mg daily). T790M was detected by cobas in 16 patients from plasma, 44 patients from tissue, 3 patients from both samples. Among assessable patients, ORR, DCR and PFS in patients with T790M positive by cobas from plasma were 66.7%, 86.7%, 194 days, those of tissue were 53.5%, 97.7%, 186 days, respectively. In these 57 patients, MBP-QP also could detect T790M from 10 patients from plasma, and ORR, DCR and PFS in patients with T790M positive by MBP-QP from plasma were 75.0%, 87.5%, 184 days, respectively. These results suggest that T790M detection from cfDNA not only by cobas but also MBP-QP is correlated with RR of osimertinib. Now, using ddPCR and Guardant360, we have been investigating about the relationship between T790M AF and RR to osimertinib, and the influence of mutations at loci other on efficacy of osimertinib.

      Conclusion

      cfDNA analysis can be predictive for osimertinib efficacy, just as re-biopsy. Whether comprehensive approach including AF and coexistence of other actionable genes is more precisely informative for drug efficacy has been continuously analyzed.

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    P2.17 - Treatment of Early Stage/Localized Disease (ID 189)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.17-28 - Examination of the Indication and Validity of Segmental Resection as Intentional and Palliative Limited Resection for Lung Cancer (Now Available) (ID 2482)

      10:15 - 18:15  |  Author(s): Hitomi Umeguchi

      • Abstract
      • Slides

      Background

      Segmental resection with lymph node dissection as intentional limited resection is now regarded as the effective surgical procedure for early lung cancer from the view point of curability and preservation of respiratory function. But the curability of this procedure for more advanced cancer is not well known. We may show it by investigating the detailed results of all segmental resection cases as intentional and palliative limited resection.

      Method

      We targeted 167 cases who passed more than five years after operation among 240 lung cancer cases on whom we have performed segmental resection with lymph node dissection between January in 2003 and March in 2019. It was decided that the indication of segmental resection as intentional limited resection was cStage 0, IA1 and IA2 (UICC 8th) with meeting the SUVmax value of FDG-PET was 1.5 or less (=group A). Segmental resection as palliative limited resection was performed on cStage IB or less patients who had difficulty in lobectomy because of poor respiratory function, multiple lung cancer or presence of serious other disease, etc, (=group B). We investigated prognosis and pathological recurrent factors in both groups, and we considered each indication of segmental resection as intentional or palliative limited resection again.

      Result

      Group A contains 102 cases and 5-year survival rate was 97% (All death cases died of other disease). In group A, local recurrence occurred in 1 case (pStage IA1, surgical margin insufficient) but distant metastasis did not occur. Group B contains 65 cases and 5-year survival rate was 71% (The original death from lung cancer was 5 cases among 17 death cases). In group B, local recurrence occurred in 4 cases (pStage IA2: 1(surgical margin insufficient), pStage IB: 2, pStage IIIA: 1), distant metastasis occurred in 6 cases (pStage IA3: 1, pStage IB: 1, pStage IIIA: 3, pStage IIIB: 1) and 3 cases on which postoperative adjuvant chemotherapy had been performed had no recurrence (pStage IB: 1, pStage IIB: 2). Recurrence of pStage IA3 was only 1 case (10% in all pStage IA3 cases, Sm, distant metastasis). The multivariable analysis of pathological recurrent factors (pStage, p, v, ly) in group B (except for 3cases on which postoperative adjuvant chemotherapy was performed) showed that lymphatic involvement had a significant influence on recurrence (p-value / Hazard ratio: lymphatic involvement: 0.03 / 6.49, more than pStage II: 0.37 / 2.50).

      Conclusion

      We are convinced that the current indication of our intentional limited resection to be almost proper but we have thought that we should include a part of Stage IA3 depending on a condition. In palliative limited resection cases, postoperative adjuvant chemotherapy should be considered if possible when pathological result show lymphatic involvement or more than pStage II.

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