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Takehiro Uemura



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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: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.01-12 - SNPs of Organic Cation Transporter 6 Associate with the Efficacy of Platinum Combination Chemotherapy (Now Available) (ID 170)

      08:00 - 18:00  |  Author(s): Takehiro Uemura

      • Abstract
      • Slides

      Background

      Platinum derivatives (cisplatin or carboplatin) are key antitumor drugs to non-small cell lung cancer in combination therapy with not only other cytotoxic agents or vascular endothelial growth factor but also kinase inhibitors or immune checkpoint inhibitors. However, the predictive biomarker of effectiveness about platinum-based chemotherapy is still unclear.

      Organic cation transporter 6 (OCT6) is one of the solute carrier transporters (coded by SLC22A16) which transport substrates by facilitated diffusion or secondary active transport. We previously reported that OCT6 was involved in platinum drug resistance by mediating platinum drug influx in cancer cell. Single nucleotide polymorphisms (SNPs) in genome sequences bring about changes in the amino acid sequence, alter the protein structure, and result in individual differences.

      The aim of this study is to solve the association between the efficacy of cytotoxic chemotherapy including platinum derivatives and SNPs.

      Method

      We retrospectively screened 78 advanced non-squamous non-small cell lung cancer patients who received platinum derivatives (cisplatin or carboplatin) and pemetrexed combination therapy for the first line chemotherapy between October/2010 and May/2018. We investigated the association between SNPs (rs714368, rs723685, and rs12210538) of SLC22A16 or patients’ characteristics and clinical outcomes.

      Result

      The median age of patients was 67 years old. Sixty patients were male and 61 patients were current or former smokers. The historical features of Sixty-eight patients were adenocarcinoma, and 18 patients had positivity of EGFR mutation or ALK fusion. We excluded rs12210538 from covariable of this study as all patients had major homo allele about rs12210538.

      The clinical outcomes of this study were similar to those of previous clinical studies.

      We found the patients with phenotype “A” of rs714368 had higher disease control rate (DCR) and longer duration of progression free survival (PFS) compared to phenotype “G” [response rate (RR), 31.4 % vs 25%, p >0.99; DCR, 85.7% vs 37.5%, p<0.01; median PFS, 154 days vs 26,5 days, p<0.01; median overall survival (OS), 666 days vs 471 days, p=0.69, respectively]. On the other hand, genotype of rs723685 had no association with treatment outcomes [genotype “TT” vs “TC”, RR, 32.8% vs 18.2%, p=0.49; DCR, 83.6% vs 63.6%, p=0.21; PFS, 132 days vs 111 days, p=0.37; OS, 558 days vs 1014 days, p=0.46]. Phenotype A of rs714368 and earlier stage were good predictive factor about PFS in Cox proportional hazard model.

      Conclusion

      Gene polymorphisms of rs714368 may change the function of OCT6 and influence the efficacy of platinum combination chemotherapy.

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      EP1.01-32 - Improving the Prognosis of Non-Small Cell Lung Cancer After the Approval of Immune Checkpoint Inhibitors: A Retrospective Analysis (Now Available) (ID 1276)

      08:00 - 18:00  |  Author(s): Takehiro Uemura

      • Abstract
      • Slides

      Background

      Anti-programmed death-1/programmed death-ligand-1 (PD-1/PD-L1) blockade represents a revolutionary breakthrough in the treatment of advanced non-small-cell lung cancer (NSCLC). However, it remains unclear whether the immunotherapy for PD-1 axis are associated with overall survival (OS) in real world patients.

      Method

      We retrospectively analyzed consecutive 246 patients with stage IIIB or IV NSCLC who underwent at least 1 regimen of chemotherapy. Patients who have EGFR mutations, ALK/ROS1 rearrangements, or received curative thoracic radiotherapy were excluded. Besides, patients administered any immune checkpoint inhibitors in clinical trials were also excluded. Treatment outcomes were compared between patients who started chemotherapy from January 2012 to December 2014 (cohort A; n=135) and those who started it from January 2016 to December 2017 (cohort B; n=111). Baseline characteristics were balanced using propensity score matching, including variables such as age, sex, performance status (PS), histology, clinical stage, bone metastases, central nervous system (CNS) metastases, liver metastases, pulmonary metastases, and pleural dissemination.

      Result

      Median OS was 11.4months in cohort A and 16.6mo in cohort B (HR 0.68, 95%CI 0.50-0.93, P=0.016). In 111 propensity-score matching pairs, median OS was 11.2months in cohort A and 16.6months in cohort B (HR 0.68, 95%CI 0.49-0.94, P=0.021), and the 12-month OS rate was 48.7% in cohort A versus 59.9% in cohort B, respectively. PD-1 axis inhibitors were received 13.5% in cohort A and 64.9% in cohort B. Forest plot for the propensity-matched patient analysis demonstrated a significantly better outcome in cohort B, for patients with PS 0 to 1, smokers, number of metastases ≤1, no bone metastases, no CNS metastases, no liver metastases, no pulmonary metastases, pleural metastases, and squamous histology.

      Conclusion

      This result indicates the appearance of immunity checkpoint inhibitors improved the prognosis of driver-mutation negative NSCLC in real world.

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    P1.12 - Small Cell Lung Cancer/NET (ID 179)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.12-17 - Association Between the Pharmacokinetics and Clinical Outcome of Amrubicin Treatment (ID 2285)

      09:45 - 18:00  |  Author(s): Takehiro Uemura

      • Abstract
      • Slides

      Background

      Amrubicin (AMR) is a key agent for small cell lung cancer (SCLC) but involves a high frequency of severe neutropenia. However, the influence of AMR pharmacokinetics (PK) on the clinical outcomes has not been fully elucidated. It was reported that organic cation transporter6 (OCT6) is one of influx transporters, and that single nucleotide polymorphism (SNP) of OCT6 effects clinical outcome of doxorubicin. In this study, we examined the PK parameters of AMR and its active metabolite, amrubicinol (AMR-OH), and whether OCT6 SNP is related to clinical outcome of AMR treatment.

      Method

      Seventy-eight lung cancer patients treated with AMR from March 2009 to March 2017 at Nagoya City University hospital were enrolled in this study. Of these 78 patients, 62 were male, 58 were SCLC and 20 were non-small cell lung cancer, and in 35 the dose of AMR were 40mg/m2 and in 43 were 30 or 35mg/m2. In 21 patients, blood samples were obtained seven times in a 24-hour after the first AMR administration, and we quantified AMR and AMR-OH concentration by a high-performance liquid chromatography assay and calculated area under curve (AUC) of AMR and AMR-OH by the liner trapezoidal rule from 0 to 24-hour. In 78 all patients, grade of neutropenia and the percent decrease in the absolute neutrophil count (ANC)* in first course of AMR treatment were investigated, and OCT6 SNP (A146G) was genotyped using Taqman genotyping assay.

      *%decrease ANC= pretreatment ANC – nadir ANC/ pretreatment ANC×100.

      Result

      The %decrease ANC was significantly related to the AUC of AMR-OH (r=0.5873, p=0.0051). The AUC of AMR-OH was significantly higher in the patients with grade4 neutropenia (608.9±47.92 ml/min) than in without grade4 neutropenia (383.8±33.75 ml/min) (p=0.0008). Of all 78 patients, classified into OCT6 SNP A146G genotype group, 26 had AA, 43 had AG, and 9 had GG. Among 21 patients examined the PK parameters, 8 had AA and 13 had AG+GG, the AUC of AMR-OH was significantly higher in AA (615.0±51.83 ml/min) than in AG+GG (397.3±35.01 ml/min) (p=0.0019). These results were same as in AMR. The incidence of grade4 neutropenia was significantly higher in patients with AA (15/26) than in patients with AG+GG (12/52) (p=0.0048).

      Conclusion

      OCT6 SNP A146G is associated with the AUC of AMR and AMR-OH, as well as affects the emergence of severe neutropenia.

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