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Akira Ono



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    MA 17 - Locally Advanced NSCLC (ID 671)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      MA 17.06 - Safety Data from Randomized Phase II Study of CDDP+S-1 vs CDDP+PEM Combined with TRT for Locally Advanced Non-Squamous NSCLC (ID 8296)

      16:20 - 16:25  |  Presenting Author(s): Akira Ono

      • Abstract
      • Presentation
      • Slides

      Background:
      Both cisplatin (CDDP)+S-1 and CDDP+pemetrexed (PEM) can be given at full systemic doses with thoracic radiotherapy (TRT) in locally advanced non-small cell lung cancer (NSCLC), and CDDP+PEM is one of the standard chemotherapy regimens in patients with advanced non-squamous (non-sq) NSCLC. This multicenter, randomized, open-label, phase II study (SPECTRA) compared the efficacy and safety of the two above-mentioned promising regimens combined with TRT in patients with unresectable locally advanced non-sq NSCLC.

      Method:
      Patients were randomly assigned to receive CDDP+S-1 (CDDP 60mg/m2, d1, and S-1 80mg/m2, d1-14, q4w, up to 4 cycles) or CDDP+PEM (CDDP 75mg/m2, d1, and PEM 500mg/m2, d1, q3w, up to 4 cycles) combined with TRT 60Gy in 30 fractions. The primary endpoint was 2-year progression-free survival (PFS) rate. If the 2-year PFS rate is assumed to be 25% in the inferior therapy group and 15% higher in the superior therapy group of this study, the sample size needed for selection of the optimum treatment group at a probability of approximately 95% will be 51 cases/group with the Simon’s selection design. The sample size was set at 100 patients.

      Result:
      Between Jan 2013 and Oct 2016, 102 patients were enrolled in this study from 9 institutions in Japan. All 102 patients were eligible and assessable, of whom 52 were assigned to CDDP+S-1 and 50 to CDDP+PEM. Baseline characteristics were similar (CDDP+S-1/CDDP+PEM): median age (range) 64.5 (39-73)/63.5 (32-74) years; women, n=17 (33%)/n=17 (34%); stage IIIB, n=21 (40%)/n=20 (40%); ECOG PS of 1, n=14 (27%)/n=14 (28%); never smoker, n=12 (23%)/n=12 (24%); and adenocarcinoma, n=47(90%)/n=45(90%). Completion rate of TRT (60Gy) and chemotherapy (4 cycles) was 92%/98% and 73%/86%, respectively. Response rate was 60%/64%. Grade 3 or higher toxicities included febrile neutropenia (12%/2%), anorexia (8%/16%), diarrhea (8%/0%), esophagitis (6%/8%), pneumonia (4%/4%), neutropenia (38%/52%), anemia (8%/12%), thrombocytopenia (4%/6%), and hyponatremia (12%/12%). Grade 1 radiation pneumonitis was observed in 8 (15%)/2 (4%) patients on the basis of the data collected 30 days or less after the discontinuation of protocol treatment. No treatment-related death was observed. The data on PFS and overall survival are immature.

      Conclusion:
      Response rate was similar between the two arms. Toxicities were tolerable and manageable in both arms; however febrile neutropenia was more frequently observed in the CDDP+S-1 arm. We will present the updated safety data of this study at the conference. Survival data will be analyzed in late 2018.

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    P2.15 - SCLC/Neuroendocrine Tumors (ID 716)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      P2.15-008 - Genomic Analysis to Assess a Molecular Signature in Japanese Patients with Pulmonary High Grade Neuroendocrine Carcinoma (ID 8912)

      09:30 - 09:30  |  Author(s): Akira Ono

      • Abstract
      • Slides

      Background:
      Pulmonary neuroendocrine carcinoma, including small cell lung cancer (SCLC), large cell neuroendocrine carcinoma (LCNEC), and carcinoid tumor, is a highly malignant cancer with poor prognosis. Because of its rarity, the molecular information available to investigate suitable therapeutic targets is insufficient, and little advancement has been made in the development of molecular-targeted therapies for these patients. This study aimed to determine a molecular signature of pulmonary neuroendocrine carcinoma by genomic analysis to explore therapeutic targets.

      Method:
      Surgically resected primary tumor specimens obtained between January 2014 and June 2016 from 15 patients with neuroendocrine carcinoma [SCLC, 8; LCNEC, 6; typical carcinoid (TC), 1; categorized based on WHO classification] were subjected to whole-exome sequencing (WES) and gene-expression profiling (GEP). Corresponding peripheral blood samples were collected as controls to identify tumor-specific genetic alterations in WES. Written informed consent was obtained from all patients. WES was performed on an Ion Proton system. An Agilent SurePrint G3 Human Gene Expression 8×60K v2 Microarray was used to detect tumor-specific gene expression. Oncogenic fusions were detected by targeted RNA sequencing. Copy number alterations were detected by integrating copy numbers resulting from WES and GEP. Promising oncogenic genetic alterations were selected using the OncodriveFML and Cancer Genome Interpreter.

      Result:
      Patient characteristics were: median age, 67 years; men, 67% (10/15); smokers, 93% (14/15); ratio of stage I/II/III/IV (%), 40/47/13/0. The median tumor mutational burden (TMB) in SCLC and LCNEC was 7.6 mutations (mt)/Mb (1.1–11.3) and 8.0 mt/Mb (3.5–12.6), respectively, which were significantly higher than that in lung adenocarcinoma (1.6 mt/Mb; p = 0.0025, p = 0.009), but not in lung squamous cell carcinoma (5.6 mt/Mb). One patient with TC showed low TMB (0.7 mt/Mb) and harbored a truncating mutation in MEN1, indicating a typical molecular signature of carcinoid tumor. The commonly altered genes (≥ 20%) were TP53 [60%, mut, 8; downregulation (down), 1], RB1 (53%, mut, 6; down, 2), CCNE1 [27%, amplification (amp), 4], APC (27%, mut, 3; down, 1), and BCL2 (20%, amp, 3). All genetic alterations detected in TP53, RB1, and APC were putative loss-of-functions. We observed no significant differences in frequency of alterations in the commonly altered genes between SCLC and LCNEC. One patient with LCNEC harbored EGFR-activating mutation, indicating possibility that this tumor was combined LCNEC with adenocarcinoma.

      Conclusion:
      This study revealed a molecular signature in Japanese patients with pulmonary neuroendocrine carcinoma, which could contribute to the development of novel molecular-targeted therapies.

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