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Masahiro Morise



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    OA02 - A New Vision of Targets and Strategies (ID 120)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      OA02.01 - Alectinib in Previously Treated RET-Rearranged Advanced Non-Small-Cell Lung Cancer: A Phase 1/2 Trial (ALL-RET) (Now Available) (ID 1651)

      10:30 - 12:00  |  Author(s): Masahiro Morise

      • Abstract
      • Presentation
      • Slides

      Background

      RET rearrangements occur in 1–2% of non-small cell lung cancers (NSCLCs). Alectinib (300 mg twice daily) has been approved for the treatment of ALK-rearranged NSCLC in Japan; it also has a high activity against RET in vitro. A global trial (ALEX study) showed the efficacy and safety of alectinib (600 mg twice daily) in ALK-rearranged NSCLC patients. We conducted a phase 1/2 study of alectinib to establish the recommended dose (RD) and examined its activity in RET-rearranged Japanese NSCLC patients.

      Method

      This study was a single-arm, open-label, multi-institutional phase 1/2 trial. RET-rearranged NSCLC patients treated with at least one regimen of chemotherapy were recruited. RET rearrangements were screened using LC-SCRUM-Japan, a nationwide genomic screening network. In phase 1, alectinib (600 or 450 mg twice daily) was administered, following a 3 + 3 design. The primary endpoint was safety. During phase 2, alectinib at the RD defined in phase 1 was administered. The primary endpoint was the objective response rate in RET inhibitor-naïve patients.

      Result

      Between March 8, 2016 and January 29, 2018, 35 patients were enrolled, and 34 patients were administered alectinib. KIF5B-RET was the most common fusion gene (22 cases [63%]), and the CCDC6-RET fusion was identified in 8 cases. The remaining 5 cases were not distinguishable. In cohort 1 (600 mg twice daily), we observed 5 DLTs (grade 3 rash, increased aspartate aminotransferase, erythema multiforme, thromboembolic event, and increased CPK) in 3 of 6 patients. In accordance with the protocol, we moved to cohort 2 (450 mg twice daily) and observed no DLTs in 3 patients. Additionally, pharmacokinetic analysis indicated that the mean exposure (AUC0–10) of 600 mg twice daily was higher than that previously reported in AF-002JG trial (global phase 1 study). Therefore, we determined 450 mg twice daily as the RD for phase 2. Twenty-five RET inhibitor-naïve patients were treated with the RD, of whom 1 achieved an objective response (4%) and 13 achieved disease control at 8 weeks (52%) as determined by central review. The median progression-free survival was 3.4 months (95% CI 2.0-5.4), and the median overall survival was 19.0 months (5.4-NE). We observed grade 3 neutropenia, pneumonitis, diarrhea, hyponatremia, increased CPK and blood bilirubin (4%) in patients treated with 450 mg alectinib twice daily; no grade 4 adverse events were observed.

      Conclusion

      Alectinib had limited activity in patients with RET-rearranged NSCLC. Further investigation of new targeted therapeutics is required to improve outcomes for these patients.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-23 - UHRF1 as a Potential Therapeutic Target for KRAS Mutated Non-Small Cell Lung Cancer (ID 687)

      10:15 - 18:15  |  Author(s): Masahiro Morise

      • Abstract

      Background

      KRAS mutation occurring in approximately 20% of non-small cell lung cancer (NSCLC) functions as a driver oncogene and it serves as a potential therapeutic target. However, development of KRAS-targeted drugs has not been successful primarily because of difficulty in pharmacologically inhibiting a constitutively activated KRAS signaling. Activation of several driver oncogenes including mutant KRAS in normal cells causes cellular senescence, leading to permanent cell cycle arrest, which is termed oncogene-induced senescence (OIS). Thus, KRAS mutated cancers are thought to acquire additional alterations that allow bypassing OIS and such alterations could be good targets for them. With this background, we designed the present study to identify therapeutic targets whose inhibition cause growth suppression in KRAS mutated NSCLC through inducing OIS.

      Method

      We established cdk4/hTERT-immortalized normal human bronchial epithelial cell (HBEC) that expresses mutant KRAS upon tetracycline treatment (designated HBEC-RIN). A semi-genome wide shRNA library (DECIPHER) targeting 5,000 genes was transduced in HBEC- RIN. Each shRNA vector is barcoded with unique sequence for quantification. Two weeks after culturing the cells, we extracted genomic DNA from cells at two points: before (point#1) and after (point #2) tetracycline treatment. The barcodes of DNA were sequenced with NGS at a depth of 20 million reads. The effects of senescence-bypass were determined by dividing the normalized barcode abundance at point #2 by that of point#1. The significance of change of each gene was determined by performing t-test to compare replicates of shRNA with a given gene with those of luciferase. Senescence was evaluated by senescence associated b-gal staining. Three KRAS mutated lung cancer cell lines (A549, H2009, and H460) were used to examine effects of silencing candidates of OIS-bypassing genes. Association between prognosis and expression of candidate genes in NSCLC patients was analyzed with several online datasets.

      Result

      We drew a volcano plot from results of a shRNA screen. We selected genes based on significant average suppressive effects. In the present study, we focused on Ubiquitin-like, containing PHD and RING finger domains, 1 (UHRF1) because we were able to confirm OIS-bypassing ability of this gene in HBEC-RIN by its transient silencing with synthetic siRNA. Colorimetric growth and colony formation assays showed that UHRF1 knockdown suppresses cell growth and colony formation in H2009 but not in A549 or H460. Importantly, we found that expression of UHRF1 mRNA correlated with worse prognosis in patients with NSCLC in multiple independent datasets, suggesting its potential as a prognostic marker.

      Conclusion

      These results suggest that UHRF1 is a potential therapeutic target for KRAS mutated NSCLC and that it is a prognostic marker for NSCLC.

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    P2.18 - Treatment of Locoregional Disease - NSCLC (ID 191)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.18-18 - Impact of Combined Evaluation Using Tumor Volume and Metastatic Nodal Extent in Stage III NSCLC Treated with CRT (ID 310)

      10:15 - 18:15  |  Author(s): Masahiro Morise

      • Abstract
      • Slides

      Background

      Chemoradiotherapy (CRT) is the standard treatment for patients with unresectable stage III non-small cell lung cancer (NSCLC). In those, gross tumor volume (GTV) and number of metastatic nodal stations were proposed as possible prognostic factors, while TNM stage classification (stage IIIA vs. stage IIIB/IIIC) did not show significant prognostic impact. However, these evidences remain controversial. The aim of this study was to investigate the prognostic impact of GTV and metastatic nodal extent.

      Method

      We retrospectively reviewed stage III NSCLC patients treated with CRT at our institution between October 2005 and December 2018. Simplified GTV (sGTV) was calculated by oval volume formula. We confirmed statistically significant association between sGTV and standard GTV as previous preparation. Metastatic nodal extent was divided into limited nodal extent (≤ND2a) (defined as "LN") or extensive nodal extent (>ND2a)(defined as "EN"). Prognostic impact of sGTV and metastatic nodal extent was evaluated by univariate and multivariate analysis.

      Result

      58 patients were enrolled in this study. Median progression-free survival (PFS) of all patients were 9.0 months. In univariate analysis, patients with sGTV>90cm3 had shorter PFS compared to those with sGTV≤90cm3 (median PFS: 6.7 vs. 11.7, p=0.03). Further, patients with sGTV>90cm3 and EN showed poorer PFS (HR 3.3; 95% CI,1.40-7.87; p<0.01) and OS (HR 3.3, 95% CI: 1.18-9.32, p<0.01) in univariate analysis. Multivariate analysis also showed an independent poor prognosis in patients with sGTV>90cm3 and EN (adjusted HR of PFS: 3.6, 95% CI: 1.49-8.71, p<0.01, adjusted HR of OS 4.1, 95% CI: 1.37-12.6, p=0.01).

      Conclusion

      Combined evaluation using sGTV and metastatic nodal extent can be a useful stratified factor for clinical trial in patients with stage III NSCLC.

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