2022/2/5 LC-SCRUM-Asiaに基づいた臨床開発希少頻度の肺癌における治療開発の難しさl l - LC-SCRUM-Asiaの活動目的2013/2 ● ● ● l ● Lung Cancer Genomic Screening Project for Individualized Medicine in Japan (LC-SCRUM-Japan) A prospective observational study to determine the pathological and molecular characteristics of RET fusion positive lung cancer l  Non-Sq NSCLC, EGFR mutation (-) Sample: 1) Fresh Frozen + FFPE or 2) Pleural Effusion Submit, to SRL, Inc. 3 Fusion Genes D REL ROS1 ALK RET fusion gene double positive by RT-PCR & FISH Study of Vandetanib for RET Positive NS I Study of Crizotinib for ROS1 Positive NSCLC (0012-01 stu Phase II Study of Vandetanib (ZD6474) in Patients with RET Fusion-positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer (LURET study) • Advanced NSCLC • RET Fusion-positive Fresh frozen (RT-PCR) and FFPE (FISH) • Age ≥ 20 years, PS 0-2 • At least one prior chemo Primary endpoint      : ORR Secondary endpoints: DCR, PFS, DR, Toxicity Number of ITT sites  : 7 institutes in Japan Enrollment: 2 years      Follow-up: 1 year Research fund: Health Labour Sciences Research Grant
Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial Kiyotaka Yoh, Takashi Seto, Miyako Satouchi, Makoto Nishio, Noboru Yamamoto, Haruyasu Murakami, Naoyuki Noqami, Shingo Matsumoto, Takashi Kohno, Koji Tsuta, Katsuya Tsuchihara, Genichiro Ishii, Shogo Nomura, Akihiro Sato, Atsushi Ohtsu, Yuichiro Ohe, Koichi Goto Summary Background RET rearrangements are rare oncogenic alterations in non-small-cell lung cancer (NSCLC). Vandetanib is a multitargeted tyrosine kinase inhibitor exhibiting RET kinase activity. We aimed to assess the efficacy and safety of vandetanib in patients with advanced RET-rearranged NSCLC. Methods In this open-label, multicentre, phase 2 trial (LURET), patients with advanced RET-rearranged NSCLC continuously received 300 mg of oral vandetanib daily. RET-positive patients were screened using a nationwide genomic screening network of about 200 participating institutions. Primary endpoint was the independently assessed objective response in eligible patients. This study is registered with UMIN-CTR, number UMIN000010095. FIndings Between Feb 7, 2013, and March 19, 2015, 1536 patients with EGFR mutation-negative NSCLC were screened, of whom 34 were RET-positive (2%) and 19 were enrolled. Among 17 eligible patients included in primary analysis, nine (53% [95% CI 28–77]) achieved an objective response, which met the primary endpoint. In the intention-to-treat population of all 19 patients treated with vandetanib, nine (47% [95% CI 24-71]) achieved an objective response. At the data cutoff, median progression-free survival was 4.7 months (95% CI 2.8–8.5). The most common grade 3 or 4 adverse events were hypertension (11 [58%]), diarrhoea (two [11%]), rash (three [16%]), dry skin (one [5%]), and QT prolongation (two [11%]). Interpretation Vandetanib showed clinical antitumour activity and a manageable safety profile in patients with advanced RET-rearranged NSCLC. Our results define RET rearrangement as a new molecular subgroup of NSCLC suitable for targeted therapy. Funding The Ministry of Health, Labour and Welfare of Japan and the Practical Research for Innovation Cancer Control from the Japan Agency for Medical Research and Development, AMED. -10 -20 iximum tumor shrinkage from baseline -30 -40 -50 -60 ■ KIF5B-RET ■ CCDC6-RET -70 -80 ■ Unknown-RET ORR 53% (90% CI, 31 to 74%) in 17 eligible patients Lancet Respir Med. 2017 Jan;5(1):42-50
Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial Alexander Drilon, Natasha Rekhtman, Maria Arcilo, Lu Wang, AndyNi, Medanie Albano, MartineVanVoorthuysen, Romel Somwar, Roger S Smith, Joseph Montecalvo, Andrew Ploakowski, Michelle S Ginsberg, Gregory) Riely, Charles M Rudin, Marc Ladanyi, Mark G Kris
Summarv
Background RET rearrangements are found in 1-2% of non-small-cell lung cancers. Cabozantinib is a multikinase inhibitor with activity against RET that produced a 10% overall response in unselected patients with lung cancers. To assess the activity of cabozantinib in patients with RET-rearranged lung cancers, we did a prospective phase 2 trial in this molecular subgroup. Methods We enrolled patients in this open-label, Simon two-stage, single-centre, phase 2, single-arm trial in the USA if they met the following criteria: metastatic or unresectable lung cancer harbouring a RET rearrangement, Karnofsky performance status higher than 70, and measurable disease. Patients were given 60 mg of cabozantinib orally per day, The primary objective was to determine the overall response (Response Criteria Evaluation in Solid Tumors version 1.1) in assessable patients; those who received at least one dose of cabozantinib, and had been given CT imaging at baseline and at least one protocol-specified follow-up timepoint. We did safety analyses in the modified intention-to-treat population who received at least one dose of cabozantinib. The accrual of patients with RET-rearranged lung cancer to this protocol has been completed but the trial is still ongoing because several patients remain on active treatment. This study was registered with ClinicalTrials.gov, number NCT01639508. FIndings Between July 13, 2012, and April 30, 2016, 26 patients with RET-rearranged lung adenocarcinomas were enrolled and given cabozantinib; 25 patients were assessable for a response. KIFSB-RET was the predominant fusion type identified in 16 (62%) patients. The study met its primary endpoint, with confirmed partial responses seen in seven of 25 response-assessable patients (overall response 28%, 95% CI 12-49). Of the 26 patients given cabozantinib, the most common grade 3 treatment-related adverse events were lipase elevation in four (15%) patients, increased alanine aminotransferase in two (8%) patients, increased aspartate aminotransferase in two (8%) patients, decreased platelet count in two (8%) patients, and hypophosphataemia in two (8%) patients. No drug-related deaths were recorded but 16 (62%) patients died during the course of follow-up. 19 (73%) patients required dose reductions due to drug-related adverse events. Interpretation The reported activity of cabozantinib in patients with RET-rearranged lung cancers defines RET rearrangements as actionable drivers in patients with lung cancers. An improved understanding of tumour biology and novel therapeutic approaches will be needed to improve outcomes with RET-directed targeted treatment. Funding Exelixis, National Institutes of Health and National Cancer Institute Cancer Center Support Grant P30 CA008748.
1st-stage SCRUM-J 2nd-stage SCRUM-J 3rd-stage SCRUM-J 2013 2014 2015 、2016
2021 EGFR mt (-) Non-Sq NSCLC ALL Non-Sq NSCLC OCA: Oncomine Comprehensive Assay OPA: Oncomine Precision Assay
Amoy MASTER Panel DNA assay (571 genes) & RNA assay (2660 genes) Comprehensive genome and transcriptome profiling from both DNA and RNA (Tissue NGS) Genexus/OPA (Tissue or Liquid NGS) MET FISH for EGFR-TKI failure or MET amp by NGSアLarge NGS panel Small NGS panel Genexus/OPA (Tissue and/or Liquid NGS) Amoy 9-1 kit Tissue PCR) Negative for 20 target genes or Mucinous Ad Whole-RNA Seq 1st-line 3rd-line 2nd-line Tx Tx Tx 3rd-stage   4th-stage Ø   OCA, OMLA Ø  AMP (large panel) 6 Germline Ø   OPA-Liquid Ø   LC-SCRUM-Support
178 institutions in 40prefectures participating  (2020/9/3-2021/
350 16000 15000 14000 13000 12000 11000' 9000 8000 7000 6000 5000 4000 3000 2000 1000
OCA
ROS1 fusion BRAF V600E NTRK1-3 fusion METex14 skipping RET fusion (approval on Mar. 25, 2020) (approval on Jun 29, 2020) (approval on Sep. 27, 2021) Wu YL et al. J Clin Oncol, 2018; Planchard D et al. Lancet Oncol, 2016; Doebele RC et al. Lancet Oncol, 2020 Paik PK et al. N Engl J Med, 2020; J Wolf et al. N Engl J Med, 2020; Drilon A et al. N Engl J Med, 2020
N Engl J Med. 2021;384:2371-81 Just approved on Jun 20, 2022!
Gefitinib Erlotinib Afatinib Osimertinib Alectinib Crizotinib Ceritinib Crizotinib  Dabrafenib  Entrectinib  Tepotinib Selpercatinib Capmatinib + Trametinib
CDx
l on PGM Dx System 46遺伝子：参考情報。現時点ではCGP
Dx Target Test CDx
9-in-1 (V1, Chinese version) AmoyDx® Multi-Gene Mutations Detection Kit: 118 variations
•  EGFR 20ins: 15 types, 58.2 % of all known types (70.8% of Asian population) •  HER2 20ins:  12 types, 91.3% of all known types (96.6% of Asian population) 9-in-1 (V2, Japanese version)
•  EGFR 20ins: 29 types, 78.1% of all known types (88.2% of Asian population) •  HER2 20ins:  14 types, 93.5% of all known types (98.9% of Asian population)
For Research Use Only. Not for use in diagnostics procedures.
2020/10/2-2021/3/31: 806 patients with every 3 tests completed
2021/6/25 approved as CDx for EGFR/ALK/ROS1/BRAF 2021/8/12 approved as CDx for MET Ex14 skipping 2021/9/3   approved as integrated CDx for EGFR/ALK/ROS1/BRAF/MET Ex14 skipping
2021/6/25 PMDA approval
AmoyDx" Pan Lung Cancer PCR Panel Receives MHLW Approval as Companion Diagnostic for 9 Targeted Therapies for Use in Patients with Advanced Non-Small Cell Lung Cancer TOKYO and XIAMEN, June 30, 2021 (GLOBE NEWSWIRE) -- Riken Genesis Co., Ltd., Amoy Diagnostics Co., Ltd., ("AmoyDx") and Precision Medicine Asia Co., Ltd. ("PREMIA") today announced that the AmoyDx' Pan Lung Cancer PCR Panel (the “AmoyDx PLC Panel”), an in vitro diagnostic reagent developed as a companion diagnostic for multiple anti-cancer agents, was approved by Ministry of Health, Labour and Welfare (MHLW) for production and marketing in Japan on June 25, 2021.

2021/8/12 PMDA approval
LC-SCRUM-ASIAの事業者は、このWC新規取得不要求[AmovDx]新羅<小万貸(ポイPC:) [送料無料]新羅～5つの治療動物病を治療し、199年～は、た新規清伝子陰断密「AmoyDx結版マルチ清伝子PCRバネル」の簡床性能源National Cancer Center HP, https://www.ncc.go.jp/jp/information/pr_release/2021/0817_1/index.html
Advanced NSCLC Genotype-matched targeted therapy
Advanced NSCLC Genotype-matched targeted therapy
*Not approved as CDx

Non-sq NSCLC (Mainly mucinous adenoca.) Negative for targetable genes by Amoy 9-1/OCA v3 RNA>100ng RNA seq RIKEN genesis Reporting to LC-SCRUM-Asia management office Reporting to sites (druggable gene alterations) NRG1 fusion Other gene fusions   NTRK1-3, FGFR2/3 etc. or NRG1 instone soli LA-128-CL01
Whole-transcriptome seq OC19520C79019575161 tocaledacycglogiacycleasiacycleasea DCTEMENTAL ADCANCERYCATAGCCAAA  GEORGETTING CONCERTION (CTROCK) RT-PCR Patient #1 Break-apart FISH
Diagnosis AmoyDx® Pan Lung Cancer PCR Panel (Tissue PCR) NGS (Liquid) Neoadjuvant Molecular Targeted Therapy Matched clinical trials KRAS inhibitor Others inhibitor I  Target population: Early stage NSCLC I  Sample Size: 10,000 patients l  Registration period: 5 years l  Observation period: 5 years Surgery Adjuvant Molecular Targeted Therapy Matched clinical trials EGFR inhibitor AmoyDx® Pan Lung Cancer PCR Panel (Tissue PCR) NGS (Tissue) collabdrative MRD analysis (Tissue and/or Liquid) RET inhibitor HER2 inhibitor KRAS inhibitor Others inhibitor LC-SCRUM-MRD ROS1 inhibitor
Global sites in the Asian countries Sample CLIA certified central Lab. in Tokyo
l  Approximately 15,000 lung cancer patients were enrolled into LC-SCRUM-Asia for 9 years. l  Various actionable gene mutations, fusions and amplifications were detected in our genomic screening. l  Through the genome screening, LC-SCRUM-Asia has contributed to the development of lung cancer precision medicine in Asia. I  LC-SCRUM-Advantage, a genomic screening platform for early-stage NSCLC who are candidates for targeted therapy in neoadjuvant and adjuvant setting will be initiated from April 2022. l  The screening platform of LC-SCRUM-Asia are now expanding to Asian countries.