2016ASCOMET通路进展研究

ASCO 2016 MET进展,Presented by:,LCMC：733个样本，所有10种驱动基因的致癌驱动基因发生率,Kris MG, et al. 2013 WCLC PL03.07.,从分子机制研究EGFR-TKI获得性耐药,EGFR 靶基因改变60%,旁路激活20%,机制不明15-20%,Nature review, Clinical Oncology Augest,2014,Presented by:,Presented by:,Abstract 9020capmatinib (INC280) 联合吉非替尼在EGFR敏感突变/cMET+NSCLC患者中一项单臂Ib/II期研究：II期临床研究结果报告,Presented by: Yi-Long Wu. Abs 9020 ASCO 2016.,研究背景,cMET特异表达在TKI获得性耐药的NSCLC患者中占1525%。INC280是高选择性cMET抑制剂，其联合EGFR-TKIs在EGFR敏感突变/ cMET+NSCLC患者中显示了临床前和初步临床活性。本研究是评估INC280 联合吉非替尼在经吉非替尼/厄罗替尼/阿法替尼治疗进展后的EGFR敏感突变合并cMET+ NSCLC患者中Ib/II期临床研究(NCT01610336)。此次报告II期剂量扩展阶段临床研究数据。,Presented by: Yi-Long Wu. Abs 9020 ASCO 2016.,研究设计 Ib/II期、单臂、开放、多中心临床研究,主要终点( II期 )：ORR次要终点( II期 ) : OS、 DoR、PFS 、AE、PK,Presented by: Yi-Long Wu. Abs 9020 ASCO 2016.,Presented by:,患者主要入组标准：年龄18岁NSCLCEGFR+（exon19del/L858R，无T790M）曾接受过EGFR TKI治疗并有可测量的临床获益耐药后cMET+（免疫组化3+, 或免疫组化2+且基因拷贝数GCN 5）ECOG PS2期望寿命3个月截至2015年9月，该研究期扩大试验共纳入83名患者。期推荐剂量（RP2D）为INC280/400mg（BID）+吉非替尼/250mg（QD）。,基线特征,截止2016年3月1日，75患者停止治疗，中位暴露时间为16.7 周,研究结果,总人群ORR 31%；DCR 81% ；mPFS 24周 (95%CI 16.624.1)GCN 6 亚组, ORR 50% DCR 84%；各亚组mPFS未成熟,研究结果,靶病灶体积的最佳缓解百分比,总体人群,各GCN亚组,不良事件,所有级别最常见AE(25)有：恶心、外周水肿、低蛋白血症、食欲减低最常见药物相关AE是恶心，发生率27%最常见3/4 AE有淀粉酶升高和脂肪酶升高，发生率均为6最常见药物相关3/4 AE是脂肪酶升高SAE发生率29%； SAE中发生率（3）较高的有：肺部感染（4级），肺炎（3级），肺栓塞（3级）药物相关SAE发生率7%,研究结论,capmatinib (INC280) 联合吉非替尼显示初步临床疗效，尤其是在高水平cMET扩增肿瘤患者中capmatinib 联合吉非替尼耐受性良好所有级别、3/4级药物相关不良反应中最多见的分别是恶心、脂肪酶升高capmatinib 与吉非替尼之间未报告有药物相互作用capmatinib 联合吉非替尼为EGFR突变合并cMET+ NSCLC患者提供了新的治疗思路,Antitumor Activity and Safety of Crizotinib in Patients with Advanced MET Exon 14-Altered Non-Small Cell Lung Cancer,1Memorial Sloan Kettering Cancer Center, New York, NY; 2University of Colorado Cancer Center, Aurora, CO; 3University of California at Irvine, Irvine, CA; 4Massachusetts General Hospital Cancer Center, Boston, MA; 5University of Pittsburgh Medical Center, Pittsburgh, PA; 6UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC; 7Pfizer Oncology, La Jolla, CA; 8Rho Inc., Chapel Hill, NCClinical Science Symposium: Actionable Mutations Redefined; Mon, Jun 06 10:09 AM 10:21 AM; Abstract 108,Alexander Drilon,1 Ross Camidge,2 Sai-Hong I. Ou,3 Jeffrey W. Clark,4Mark A. Socinski,5Jared Weiss,6 Gregory J. Riely,1 Maria Winter,7Sherry C. Wang,7 Katherine Monti,8 Keith Wilner,7 Paul K. Paik1,Presented by: Alexander Drilon MD,Presented by:,MET Exon 14-Altered Lung Cancers,Incidence 3-4% of nonsquamous NSCLCs 20-30% of sarcomatoid lung carcinomas Clinicopathologic Features older patients proportion of never smokers patients should be screened regardless of these clinical features 15-20% with concurrent MET amplification,MET exon 14,indels,Paik PK et al. Cancer Discov 2015;5. Awad MM et al. J Clin Oncol 2016;34. Tong et al. Clin Cancer Res 2016. TCGA Research Network. Nature. 2014;511. Ou SI et al. ASCO 2016 Abstract 9021.,Presented by: Alexander Drilon MD,Diagnosis DNA-based next-generation sequencing RNA sequencing IHC alone is insufficient,Crizotinib,potent MET inhibitor ATP-competitive tyrosine kinase inhibitor, IC50 11 nM for MET approved for the treatment of ALK- and ROS1-rearranged lung cancers active in tumors harboring MET exon 14 alterations cell proliferation and downstream signaling in vitro case reports of patient responses,Wu P et al. Trends Pharmacol Sci 2015;36. Liu et al. J Clin Oncol 2016;34 (7). Paik PK et al. Cancer Discov 2015;5. Awad MM et al. J Clin Oncol 2016;34 (8).,Presented by: Alexander Drilon MD,Antitumor Activity, of the 5 patients: 2 awaiting confirmation, 3 cannot be confirmed this patient discontinued therapy in cycle 1, response imaging could not be performed but response-evaluable per protocol,Presented by: Alexander Drilon MD,Antitumor Activity,Maximum Response to Crizotinib in Patients with MET Exon 14-Altered Lung Cancers (n=16 with measurable disease at baseline and 1 response assessment scan),Partial response (PR), confirmedStable disease (SD): includes 4 unconfirmed PRs,*,*,* Stable disease and 0% change from baseline,Presented by: Alexander Drilon MD,Antitumor Activity,Partial response (PR), confirmedStable disease (SD): includes 4 unconfirmed PRs,*,*,MET Exon 14 Alteration Co-Occurrence with High-Level MET Amplification,concurrent MET Amplification,Central testing for both MET exon 14 alterations and high-level MET amplification via ThermoFisher Scientific Inc., Ion Torrent (Cancer Genetics, CA),Presented by: Alexander Drilon MD,Summary and Conclusions,本研究中93.8%（15/16）患者仅有MET 14外显子突变，与MET扩增不重叠，提示MET 14外显子突变与MET扩增在大部分病例中是两个相互独立、可分别使用药物治疗的生物标志物。,Presented by: Alexander Drilon MD,Abstract：9021携带MET外显子14改变的不同组织学类型的298例肺癌基因组综合分析,Sai-Hong Ignatius Ou.et al. ASCO 2016 Abstract 9021.,背景,最近MET基因外显子14跳跃缺失突变（METex14）成为MET抑制剂的潜在靶点。然而，大样本的携带METex14改变的肺癌患者研究尚未见报道。,Sai-Hong Ignatius Ou.et al. ASCO 2016 Abstract 9021.,方法,从236个癌症相关基因和19个基因的47内含子中采用杂交捕获的技术得到至少3769个外显子，这些外显子在癌症通常是重排的样品统一进行前瞻性高通量测序（平均820X），并作为常规的临床工作的一部分（2012年8月 - 2015年11月）患者样品通过基因组改变（GAs）评价，包括碱基对取代，插入/删除，拷贝数变化和重排进行评价。然后这些GAs再进行人工检查，以找出那些可能影响到MET14号外显子剪接的，或者整个删除这个外显子比较关系用Mann-Whitney U检验进行了检验;使用Pearson卡方检验与Yates连续性校正检查明确关系,Sai-Hong Ignatius Ou.et al. ASCO 2016 Abstract 9021.,方法,1)DNA/RNA 提取,2)分子捕获技术,3)分析技术,4)临床报告,Sai-Hong Ignatius Ou.et al. ASCO 2016 Abstract 9021.,基线特征,组织学类型N（%）：腺癌 205（68.8）腺鳞癌8（2.7）鳞癌25（8.4）大细胞癌2（0.7）肉瘤8（2.7）小细胞1（0.3）NSCLC NOS 49（16.4）,Sai-Hong Ignatius Ou.et al. ASCO 2016 Abstract 9021.,基线特征,剪接供体(Splice donor site, SD)、剪接受体(Splice acceptor site, SA)，non-c：non-coding非编码;indel; insertion and deletion，插入缺失；sub:substitution替换,Sai-Hong Ignatius Ou.et al. ASCO 2016 Abstract 9021.,基线特征,Sai-Hong Ignatius Ou.et al. ASCO 2016 Abstract 9021.,根据患者临床和分子特征比较METex14 NSCLC有或无并发MET扩增,Sai-Hong Ignatius Ou.et al. ASCO 2016 Abstract 9021.,根据患者临床和分子特征比较METex14 NSCLC有或无并发MET扩增,Sai-Hong Ignatius Ou.et al. ASCO 2016 Abstract 9021.,患者临床和分子特征比较METex14NSCLC有或无并发MET扩增,Sai-Hong Ignatius Ou.et al. ASCO 2016 Abstract 9021.,携带有METex14的腺癌患者克唑替尼治疗前