がん個別化医療実現のための課題 - pmda.go.jp

1 2013/11/15 PMDAPMDA 1 Driver gene fraction Approvedand Potentially effective molecular targeting agents CrizotinibLapatinibVemurafenibTemsirolim usSelumetinibCrizotinibVandetanib, Sorafenib,CabozantinibGefitinib, Erlotinib, AfatinibHER2 ALK fusionsBRAFPIK3 CAAKT1 MAP2K1 NRASROS1 fusionRET fusion*KRASEGFR unknown*KohnoT et al, Nature Medicine 18; 375-77, 20122genomepre-screening LCIHCpre-screening GCComprehensive analysis for prescreening is necessaryMolecular profile-guided therapy: 3 RET RET KIF5 BRET 10 (Kohno et al., Takeuchi et al., Lipson et al., Nat Med, 2012) 30 (NCC ) RNA 2% RET RET 4 1% ALK 1/5 1500 -2000 EPOC 1301:RET Vandetanib II :LURET RET RT-PCRFFPE FISH DNA 20 ECOG PS0- 2 1 Vandetanib300mg/day1 1 28 1 Primary endpoint Secondary endpoints PFS OS 17 70% 40% 80% 2 1 5 24 : 5 RET LC-SCRUM-JapanAnother new agent studies for ROS1, BRAF, EGFR-TKI resistant being planned using this system19/01/2013 kick off meeting in TokyoAccrual No331 120 ALK/RET/ ROS1 PI.

2 K Goto(NCCC-East)6 RET 7 1 negative ABC study cancer encyclopedia NGS 89 From single mutations to multiplex hotspot evaluationsin multiple cancer AmpliSeq Comprehensive Cancer Panel Multiplex mutation analyses will broaden the personalized 201220132014 200100050150140 42 22 17 12 ( 19 )AKT AKT1 (ABC study & TOP-GEAR study) in house cisCall Druggable 11 ABC-studySamplesMean number of mutationsRecurrently mutated genesexcept for silent (8/26)STK11(6/26)PIK3CA(3/26) (8/18)TP53(7/18)APC(7/18) (6/11)EGFR(3/11)PIK3CA(1/11) (7/9)TP53(2/9)ERBB2(1/9) (5/8)TP53(3/8)GNAS(1/8) total, mutations per sample (N=93)NCC-EastABC studyBando H, et al: JSMO 20131212 NCC Oncopanelver.

3 2: coming soon90 mutated gene and 10 fusion geneMutationAmplificationDeletionFusion1 2345678910111213141516171819202122232425 2627282930313233343536373839404142434445 4647484950515253545556575859606162636465 6667686970717273747576777879808182838485 8687888990F1F2F3F4F5F6F7F8F9F10 GeneABL1 AKT1 AKT2 AKT3 ALKAPCARID1 AARID2 ATMAXIN1 BAP1 BARD1 BCL2L11 (BIM)BRAFBRCA1 BRCA2 CCND1 CDK4 CDKN2 ACHEK2 CREBBPCTNNB1 CUL3 DDR2 EGFRENO1EP300 ERBB2 ERBB3 ERBB4 EZH2 FBXW7 FGFR1 FGFR2 FGFR3 FGFR4 FLT3 HRASIDH1 IDH2 IGF1 RIGF2IL7 RJAK1 JAK2 JAK3 KEAP1 KITKRASMAP2K1 MAP2K4 MAP3K1 MAP3K4 MDM2 METMTORMYCMYCNNF1 NFE2L2 NOTCH1 NOTCH2 NOTCH3 NRASNRG1NT5C2 PALB2 PBRM1 PDGFRAPDGFRBPIK3 CAPIK3R1 PTCH1 PTENRAC1 RAC2 RAD51 CRAF1RB1 RETROS1 SETD2 SMAD4 SMARCA4 SMOSTAT3 STK11TP53 TSC1 VHLALK fusionRET fusionROS1 fusionFGFR2 fusionFGFR3 fusionAKT3 fusionBRAF fusionRAF1 fusionNotch1 fusionNRG1 fusionDrugABL inhibitorAKT inhibitorAKT inhibitorAKT inhibitorALK inhibitorSRC inhibitor?

4 SRC inhibitorPARP inhibitor?PARP inhibitor?TKI resistantBRAF inhibitorPARP inhibitorPARP inhibitorHDAC inhibitor SRC inhibitorDNA damaging agent DasatinibEGFR inhibitorEnolase inhibitorHDAC inhibitor HER2 inhibitor ERBB inhibitorERBB inhibitorEZH2 inhibitorFGFR inhibitorFGFR inhibitorFGFR inhibitorFLT inhibitorMEK inhibitor?IDH inhibitorIDH inhibitorIGFR inhibitorIGFR inhibitorJAK-STAT inhibitorJAK inhibitorJAK inhibitorJAK inhibitorDNA damaging agent KIT inhibitorEGFR Ab resistant MEK inhibitor?MEK inhibitor?MEK inhibitor?MEK inhibitor?MDM2 antagonistMET inhibitormTOR inhibitorAurora B inhibitor?CDK2 inhibitorHSP90 inhibitorDNA damaging agent -secretase inhibitor? -secretase inhibitor? -secretase inhibitor?MEK inhibitor?HER2 inhibitorChemo-resistantPARP inhibitor?.PDGFR inhibitorPDGFR inhibitorPI3K inhibitorPI3K inhibitorSMO antagonistmTOR inhibitor?PARP inhibitor?RAF inhibitor ALK inhibitor.

5 SMO antagonistJAK-STAT inhibitormTOR inhibitor?.mTOR inhibitorGLUT1 inhibitorALK inhibitor RET inhibitorALK inhibitorFGFR inhibitorFGFR inhibitorAKT inhibitorBRAF inhibitorRAF inhibitor -secretase inhibitorHER2 inhibitorActionable111111111111111111111 1111111111111111111111111111111111111111 11111111111111111111111 Foundation cancer ca11111100110001111111111100011000111111 100010001111111111111111111 Gastric ca1111111111 Hepatocellular ca111111111111 Renal cell ca (CC)111111111 Colorectal ca11111100011100011000111 Breast ca111111111000111111111111 Panc ca111111111111 Glioma1000110001001110001111111 Medulloblastoma111000100011111 Melanoma111111111 Ovarian ca (CC)1111 Bladder TCC11111111111 Prostate ca11111 Head and neck ca1000111111111 GIST11 Leukemia1111111111111111111 Lymphoma111111111By Ichikawa H & Kohno T13 Cost reduction of NGS analysis $1,000 genome achieved?MacConaillL, et al: J ClinOncol, 201314 NGS validation ISO CAP CLIA validation NGS Incidental finding