高通量测序培训班6.2-靶向药物临床研究新进展-下篇-1

1、肺癌靶向药物研发与精准医学：下篇张绪超华南理工大学 临床医学中心广东省医学科学院 & 广东省人民医院广东省肺癌研究所 华南临床基因检测中心未来更广泛的分子分型及疾病理解Focus on TCGA Pan-Cancer Analysisby TCGA Pan-cancer analysis working group 500 selected functionalevents (SFEs) 3299 TCGA tumorsCiriello G, et al. Nature Genetics 2013Characteristic patterns of functional alterations

2、 and distinct oncogenic processesas determinants of oncogenic signature classes (OSCs).Nature Genetics, 2013, 45:1127113312个瘤种存在共同的oncogenic signatures存在直接或间接的靶向联合combinationNature Genetics, 2013, 45:1127113333个瘤种的多维数据iCluster分析 An integrative dataclustering method isapplied to reclassifyhuman tumor

3、s Cell-of-origininfluences, but doesnot fully determine,tumor classification Immune features andcopy-numberaberrations define themost mixed tumorgroups Multi-cancer groupsreveal new featureswith potential clinicalutilityHoadley et al., 2018, Cell 173, 29130433个瘤种的28 iClusters与信号通路Hoadley et al., 201

4、8, Cell 173, 291304 Alteration map of 10signaling pathwaysacross 9,125 samplesfrom 33 cancer types Reusable, curatedpathway templates thatinclude a catalogue ofdriver genes 57% of tumors have atleast one potentiallyactionable alteration inthese pathways Co-occurrence ofactionable alterationssuggests

5、 combinationtherapy opportunitiesSanchez-Vega et al., 2018, Cell 173, 321337Every patient is unique: precisely annotated!Toward Precision Medicine: Building a Knowledge Network for BiomedicalResearch and a New Taxonomy of Disease (2011)多臂临床试验：- 更多药、更多靶点、更多瘤种两类实验设计: Basket vs UmbrellaAACR cancer prog

6、ress report, 2014多基因分型: Long tail phenomenonFoudnationOneTM: NGS (14-17天)基于分子靶点的临床和转化性研究 NCI NCORP: Lung_MAP, ALCHEMIST, andMATCH trials ASCO：TAPUR NEJM： VE-BASKET trial China: lung cancer cluster trial2011 ASCO blueprint for transforming clinical and translational cancer research； 2015 ASCOLUNG-MAP

7、: Phase II/III Biomarker-driven Master Protocol forSecond Line Therapy of Squamous Cell Lung Cancer (SCCA)Common Broad PlatformCLIA Biomarker Profiling*Non-matchCT*PD-L1drugPI3KM:PIK3CA mutCDK4/6M:CCND1, Cdk6 ampl,CDKN2 del, mutFGFRM: FGFR ampl,mut, fusionHGFM:c-Met ExprDPI3KiCT*Cdk4/6 iCT*FGFRi+CTC

8、T*HGFi+EE*Endpoint(Interim PFS)OSEndpoint(Interim PFS)OSEndpoint(Interim PFS)OSEndpoint(Interim PFS)OSTT=Targeted therapy, CT=chemotherapy (docetaxel or gemcitabine), E=erlotinib*Archival FFPE tumor, fresh CNB if neededFinal agent and specific protocol arms TBA Nov 7, 2013-Friends Brookings Meeting,

9、Washington D.C.2013 WCLC, Vali PapadimitrakopoulouThe Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials, orALCHEMISTALCHEMIST - Screening component (A151216) Coordinated by theAlliance for Clinical Trials in Oncology; Principal Investigators: Pasi A.Janne, M.D., Ph.D., and

10、Geoffrey Oxnard, M.D., Dana-Farber CancerInstitute, Boston./clinicaltrials/NCT02194738ALCHEMIST - EGFR Treatment component (A081105) Coordinated bythe Alliance for Clinical Trials in Oncology; Principal Investigator:Ramaswamy Govindan, M.D., Washington University, St. Louis./clinicaltrials/NCT021932

11、82ALCHEMIST - ALK Treatment component (E4512) Coordinated byECOG-ACRIN; Principal Investigator: David E. Gerber, M.D., University ofTexas Southwestern Medical Center at Dallas./clinicaltrials/NCT02201992NIH announces the launch of 3 integrated precision medicine trials; ALCHEMISTis for patients with

12、 certain types of early-stage lung cancerNCI-MATCH trialMolecular Analysis for Therapy Choice (NCI-MATCH) ECOG-ACRIN ECOG-ACRIN Cancer Research Group website, the source of information about thecooperative group that was formed by the merger of the Eastern Cooperative Oncology Group(ECOG) and the Am

13、erican College of Radiology Imaging Network (ACRIN). NCIs National Clinical Trials Network the Alliance for Clinical Trials in Oncology NRG Oncology NRG Oncology is a non-profit research organization formed to conductoncologic clinical research and to broadly disseminate study results forinforming c

14、linical decision making and healthcare policy It brings together the National Surgical Adjuvant Breast and Bowel Project(NSABP), the Radiation Therapy Oncology Group (RTOG), and theGynecologic Oncology Group (GOG)each recognized internationally as aresearch leader. SWOG NCI Community Oncology Resear

15、ch Program (NCORP)MATCH试验特点多中心、多基因、多瘤种、多药物 2015.07启动10个臂 3,000 patients initially. 20 to 25药物 新技术分析多分子靶点 2,400 clinical sites across the United States driver mutations in more than one tumor typeInitial Actionable Mutations and Matching DrugsEstimated MutationPrevalenceDrug(s)Molecular Target(s)Criz

16、otinibCrizotinibALK rearrangementROS1 translocations4%5%BRAF V600E or V600KmutationsDabrafenib and Trametinib7%BRAF Fusions/ Non-V600E/Non-V600K BRAFmutationsTrametinib2.8%AfatinibAfatinibEGFR activating mutationsHER2 activating mutations1-4%2-5%EGFR T790M mutations andrare EGFR activatingmutationsA

17、ZD92911-2%Ado-trastuzumab emtansine HER2 amplification5%VS6063SunitinibNF2 loss2%4%cKIT mutations2015 ASCOs TAPUR trial :Targeted Agent and Profiling Utilization Registry At launch, TAPUR will evaluate 10-15 drugs contributed by 5pharmaceutical companies The primary endpoint : ORR; other endpoints:

18、PFS, OS TAPUR will launch at clinical sites within the Michigan CancerResearch Consortium, the Cancer Research Consortium of WestMichigan, and the Carolinas Healthcare System, with the goal ofexpanding nationally.10. 免疫靶向治疗2011-2018Anti-CTLA4Anti-PD1Anti-PDL12012 Nat Rev drug discovery, W. Joost Les

19、terhuis and Cornelis J. A. Punt2012 Nat Rev drug discovery, W. Joost Lesterhuis and Cornelis J. A. PuntKey studies for IO in NSCLC:establishment of SOCCheckMate 017Keynote 024CheckMate 057OAKPACIFIC：III期不可切除的非小细胞肺癌患者同步放化疗后新的治疗选择Durvalumab巩固治疗Durvalumab(N=476)Placebo(N=237)Median PFS (95% CI), months

20、12-month PFS rate (95% CI)18-month PFS rate (95% CI)16.8 (13.018.1)55.9% (51.060.4)5.6 (4.67.8)35.3% (29.041.7)1.00.90.80.70.60.50.40.30.20.10.044.2% (37.750.5)27.0% (19.934.5)分层HR, 0.52 (95% CI, 0.420.65)P0.001Two-sided P2年TSC1 E636fsinactivating mutationsIyer G, Science. 2012 October 12; 338(6104)

21、: 221例2：mTOR 信号通路变异与药物敏感性 Phase I试验 Urothelial Cancer Everolimus CR 14个月mTOR E2419K and mTOR E2014Kactivating mutationsWagle N, Cancer Discov. 2014 May;4(5):546-53Signaling Pathway vs. 药物精准治疗信号通路分型Genetic Heterogeneity may affect the same Signaling Pathway indifferent branchesPTENPIK3CAPTENPTENmTORP

22、IK3CA Genetic heterogeneity may impact the same signalling pathway in different branches PI3K/PTEN/mTORFrom data of C. SwantonGenetic Heterogeneity may affect the same Protein Complex indifferent branchesSWI/SNF Chromatin remodeling ComplexPBRM1PBRM1 and ARID1SMARCA4From data of C. Swanton肺癌异质性与进化国外

23、最前沿相关研究 ：TRACERxClinical questions Intratumor heterogeneity and survival Mutation vs CNV Causes of intratumor heterogeneity Genome doubling Chromosomal instability Mutational process Census of clonal and subclonal drivers Trunk Shared PrivateHeterogeneity revealed by Exome NSCLC SequencingHeatmaps o

24、f non-synonymous mutations% Heterogeneous Mutations31%L00161%L002L003L00443%31%L008L01125%5%DNA Copy Number Alterations: Source of NSCLC DiversityHeterogeneousUbiquitous67%78%51% 60% 88%L01L03L04 L08 L11L01L03L04 L08 L112017! predictors of ctDNA release vs tumor volume Adjuvant chemotherapy resistan

25、ce and patients destinedto experience recurrence of their lung cancer phylogenetic ctDNA profiling tracks the subclonal natureof lung cancer relapse and metastases, providing a newapproach for ctDNA driven therapeutic studiesTRACERx study Driver mutations in EGFR, MET, BRAF, and TP53 were almostalwa

26、ys clonal. heterogeneous driver alterations that occurred later in evolutionwere found in more than 75% of the tumors and were common inPIK3CA and NF1 and genes in chromatin modification and DNAdamage response and repair. Genome doubling and ongoing dynamic chromosomal instabilitywere associated wit

27、h intratumor heterogeneity and resulted in parallelevolution of driver somatic copy-number alterations, includingamplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with anincreased risk of recurrence or deathIntratumor heterogeneityMutations vs DFS红色：亚克隆性的蓝色：克隆性的CNVs vs DFS平行进化临床意义： 样本取材的代表性 耐药靶点TRACERx Renal快速进展减缓进展染色体复杂性瘤内异质性Turajlic et al., 2018, Cell 173, 114DARWIN Clinical ProgramDecipher