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Noriko Yanagitani



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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  |  Presenting Author(s): Noriko Yanagitani

      • 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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    P2.09 - Pathology (ID 174)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.09-10 - INSM1 Is a Good Marker for Diagnosis of Small Cell Lung Carcinoma Even When Neuroendocrine Marker Negative (Now Available) (ID 1104)

      10:15 - 18:15  |  Author(s): Noriko Yanagitani

      • Abstract
      • Slides

      Background

      To diagnose small cell lung carcinoma (SCLC), neuroendocrine (NE) phenotype markers such as chromogranin A, synaptophysin and CD56 are helpful. However, because they are dispensable, SCLCs occur without neuroendocrine phenotypes. Insulinoma-associated protein 1 (INSM1) is a transcription factor for neuroendocrine differentiation and has emerged as a single practical marker for SCLC.

      Method

      Using the surgical samples of 141 NE tumors (78 SCLCs, 44 large cell neuroendocrine carcinomas (LCNECs), and 19 carcinoids), and 246 non-NE carcinomas, we examined the immunohistochemical expression and prognostic relevance of INSM1 in association with NE phenotype markers in each histologic type. We evaluated its sensitivity and specificity for SCLC diagnosis, as well as its usefulness to diagnose SCLC without NE marker expression and to estimate the prognosis of the subgroups of SCLC stratified by the expression levels of the NE markers. Those of 13 lung cancer cell lines (9 SCLCs and 4 ADCs) were also evaluated.

      Result

      INSM1 was expressed in SCLCs (92%, 72/78), LCNECs (68%, 30/44), and carcinoids (95%, 18/19). Additionally, among SCLCs with no expression of NE phenotype markers (n=12), 9 (75%) were positive for INSM1. These data suggest the superiority of INSM1 to the phenotype markers. SCLC with low INSM1 expression (n=28) had a significantly better prognosis (P=0.040) than the high-INSM1 group (n=50). Only 7% of adenocarcinomas (9/134) and 4% of squamous cell carcinomas (4/112) were positive for INSM1. In cell lines, most SCLCs were positive for INSM1 (7/9), whereas all ADCs were negative (0/4).

      Conclusion

      Our study revealed that INSM1 is highly sensitive to detect SCLC, is positive in most phenotype marker-negative SCLCs and can estimate prognosis. INSM1 will be a promising marker for SCLC. 

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