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H. Yamaguchi



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    P1.03 - Chemotherapy/Targeted Therapy (ID 689)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P1.03-015 - The Relationship between the UGT1A1*27 and UGT1A1*7 Genetic Polymorphisms and Irinotecan-Related Toxicities in Patients with Lung Cancer (ID 7500)

      09:30 - 09:30  |  Author(s): H. Yamaguchi

      • Abstract

      Background:
      Genetic polymorphisms in the UDP-glucuronosyltransferase 1A1 (UGT1A1), UGT1A7, and UGT1A9 genes are associated with interindividual differences in irinotecan toxicities. Purpose: To evaluate the effects of gene polymorphisms, including UGT1A1*7, *27, and *29, on the safety of irinotecan therapy.

      Method:
      The eligibility criteria were as follows: lung cancer patients who were scheduled to undergo irinotecan therapy, aged ≥20 years, and had a performance status of 0-2. After informed consent had been obtained, patients were enrolled, and their blood was collected and used to examine the frequency of the UGT1A1*6, *7, *27, *28, and *29 polymorphisms and the drug concentrations of irinotecan, SN-38, and SN-38G after irinotecan therapy.

      Result:
      Thirty-one patients were enrolled. The patients’ characteristics were as follows: male/female = 25/6, median age (range) = 71 (55-84), stage IIB/IIIA/IIIB/IV = 2/6/11/12, and Ad/Sq/Sm/Oth = 14/10/3/4. The -/-, *6/-, *7/-, *27/-, *28/-, and *29/- UGT1A1 gene polymorphisms were observed in 10 (32%), 10 (32%), 2 (6%), 2 (6%), 7 (23%), and 0 (0%) cases, respectively. There were no homozygous or complex heterozygous polymorphisms. The UGT1A1*27 polymorphism occurred separately from the UGT1A1*28 polymorphism. The lowest leukocyte counts of the patients with the UGT1A1*27 and UGT1A1*6 gene polymorphisms were lower than those seen in the wild-type patients. SN-38 tended to remain in the blood for a prolonged period after the infusion of irinotecan in patients with the UGT1A1*27 or UGT1A1*28 polymorphism. No severe myelotoxicity was seen in the patients with UGT1A1*7.

      Conclusion:
      UGT1A1*27 and UGT1A1*7 are both rare gene polymorphisms. UGT1A1*27 can occur separately from UGT1A1*28 in some circumstances and is related to leukopenia during irinotecan treatment. UGT1A1*7 is less relevant to irinotecan-induced toxicities, and UGT1A1*29 seems to have little clinical impact.

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    P1.08 - Locally Advanced NSCLC (ID 694)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      P1.08-006 - Phase I/II Study of Carboplatin, nab-paclitaxel, and Concurrent Radiation Therapy for Patients with Locally Advanced NSCLC. (ID 8356)

      09:30 - 09:30  |  Author(s): H. Yamaguchi

      • Abstract

      Background:
      A regimen of weekly paclitaxel plus carboplatin (CBDCA) with concurrent thoracic radiotherapy is recognized as standard for patients with unresectable stage III lung cancer. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a cremophor-free formulation of paclitaxel to increase solubility and intratumor drug delivery and is effective for patients with advanced NSCLC. The purpose of this study is to determine recommended dose and investigate the efficacy and safety profile of a regimen of nab-PTX plus CBDCA with concurrent thoracic radiotherapy for patients with unresectable non-small cell lung cancer (NSCLC).

      Method:
      Patients with unresectable stage IIIA or IIIB NSCLC, good performance status, age between 20 and 74 years, and adequate organ function, a relative volume of normal lung receiving a dose of ≥ 20 Gy (V20) ≤35% were eligible. In a phase I study (standard 3+3 design), weekly nab-PTX plus CBDCA was administered intraveneously for six weeks. Doses of each drug were planned as follows: level 1, 40/2; level 2, 50/2 (nab-PTX [mg/m[2]] / CBDCA [area under the plasma concentration time curve (AUC) mg/ml/min]). Concurrent thoracic radiotherapy was administered in 2 Gy fractions to a total dose of 60 Gy. Dose-limiting toxicity (DLT) was observed during concurrent chemotherapy and thoracic radiation and up to 28 days following the end of radiotherapy. After the evaluation of DLT, patients received an additional two cycles of consolidation chemotherapy that consisted of 3-week cycles of nab-PTX (100 mg/m[2] on Days 1, 8 and 15) plus CBDCA (AUC 6 mg/ml/min on Day 1). In a phase II study, we planned to enroll 50 patients treated with recommended dose.　

      Result:
      In a Phase I study, 11 patients were enrolled and received treatment per protocol, with 9 evaluable for efficacy and toxicity. At nab-PTX dose level 1 (40mg/m[2]), none of 3 patients experienced DLT. At nab-PTX dose level 2 (50mg/m[2]), 1 of 6 patients experienced DLT: grade 3 leukopenia requiring a second consecutive skip in the administration of weekly nab-PTX plus CBDCA. The recommended doses (RDs) for the phase II study were nab-paclitaxel 50 mg/m[2] and CBDCA (AUC=2). From October 2015 to November 2016, a total of 52 patients were entered in the phase II portion ( median age, 66 years; age range, 48–74 years; male/female 44/8) .

      Conclusion:
      Concurrent chemoradiotherapy with nab-PTX 50 mg/m[2] and CBDCA AUC 2 was the recommended dose. We will report the latest efficacy and safety profile of the present therapy. Trial registration: UMIN000012719.

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    P2.07 - Immunology and Immunotherapy (ID 708)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P2.07-045 - A Retrospective Analysis of Nivolumab-Related Pneumonitis in Non-Small Cell Lung Cancer Patients (ID 10051)

      09:30 - 09:30  |  Author(s): H. Yamaguchi

      • Abstract

      Background:
      Nivolumab is a human IgG4 monoclonal antibody that targets programmed cell death-1 (PD-1). In advanced non-small-cell lung cancer patients, nivolumab has been well tolerated. However, some patients develop nivolumab-related pneumonitis.

      Method:
      We retrospectively analyzed the clinical features and prognosis of nivolumab-related pneumonitis in non-small cell lung cancer patients in the institutions of the Nagasaki Thoracic Oncology Group.

      Result:
      From January 1, 2016 to May 31, 2017, 101 non-small cell lung cancer patients were treated with nivolumab monotherapy and 8 patients (7.9%) developed nivolumab-related pneumonitis. 7 were male, and 1 was female, with a median age of 70 years. The histological subtype was squamous cell carcinoma in 3 patients, non-squamous cell carcinoma in 5 patients. 6 patients were stage III or IV. 2 patients were postoperative recurrence. Radiographic pattern was cryptogenic organizing pneumonia (COP) in 6 patients and acute interstitial pneumonia (AIP)/acute respiratory distress syndrome (ARDS) in 2 patients. The median time from nivolumab treatment initiation to development of pneumonitis was 8.5 weeks (range, 1-16). 2 patients of AIP/ARDS pattern developed pneumonitis within 2 weeks. Bronchoalveolar lavage conducted in 4 patients and bronchoalveolar lavage fluid revealed elevation of lymphocyte in all patients. All patients received corticosteroids. 6 patients of COP pattern had clinical and radiographic improvement. 2 patients of AIP/ARDS pattern worsened clinically and died during the course of pneumonitis treatment. One of patient experienced recurrent pneumonitis in the course of corticosteroid taper.

      Conclusion:
      We retrospectively analyzed the clinical features and prognosis of nivolumab-related pneumonitis in non-small cell lung cancer patients. Nivolumab-related pneumonitis showed variable onset and radiographic patterns. COP pattern was most common. Most patients were successfully treated with corticosteroids, but AIP/ARDS pattern was risk of poor prognosis.

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    P3.15 - SCLC/Neuroendocrine Tumors (ID 731)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      P3.15-001 - The Impact of MET Inhibition on Small-Cell Lung Cancer Cells Exhibiting Aberrant Activation of the HGF/MET Pathway (ID 7898)

      09:30 - 09:30  |  Author(s): H. Yamaguchi

      • Abstract

      Background:
      Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers, and is characterized as being extremely aggressive, often displaying rapid tumor growth and multiple organ metastases. In addition, the clinical outcome of SCLC patients is poor due to early relapse and acquired resistance to standard chemotherapy treatments. Several molecular targeted therapies were evaluated in SCLC; however, they failed to improve the clinical outcome. The receptor tyrosine kinase MET is a receptor for hepatocyte growth factor (HGF). Although aberrant activation of HGF/MET signaling is known as one of the crucial mechanisms enabling cancer progression and invasion, the mechanisms in SCLC have not been elucidated clearly. The aim of the present study was to evaluate the effect of inhibiting the HGF/MET pathway on tumor progression in SCLC with multi-organ metastasis.

      Method:
      We used eight human SCLC cell lines to elucidate the effect of MET inhibition on tumor progression. MET inhibitors, crizotinib and golvatinib, were used in this study in vitro and in vivo.

      Result:
      We found that the HGF/MET signaling was aberrantly activated in chemo-resistant or chemo-relapsed SCLC cell lines (SBC-5, DMS273, and DMS273-G3H) by the secretion of HGF and/or MET copy number gain. HGF/MET inhibition, induced either by MET inhibitors (crizotinib and golvatinib), or by siRNA-mediated knockdown of HGF or MET, constrained growth of these SCLC cells via the inhibition of ERK and AKT signals. We also revealed that treatment with either crizotinib or golvatinib in vivo suppressed the systemic metastasis of SBC-5 cell tumors in NK cell-depleted SCID mice, predominantly via cell cycle arrest.

      Conclusion:
      These findings reveal that the therapeutic potential of targeting the HGF/MET pathway for inhibition, to constrain tumor progression of SCLC cells exhibiting aberrant activation of HGF/MET signaling. We suggest that it would be clinically valuable to further investigate HGF/MET-mediated signaling in SCLC cells.