2016ASCOMET通路進展研究.ppt

ASCO 2016 MET進展,Presented by:,LCMC：733個樣本，所有10種驅(qū)動基因的致癌驅(qū)動基因發(fā)生率,Kris MG, et al. 2013 WCLC PL03.07.,從分子機制研究EGFR-TKI獲得性耐藥,EGFR 靶基因改變 60%,旁路激活20%,機制不明 15-20%,Nature review, Clinical Oncology Augest,2014,Presented by:,Presented by:,Abstract 9020 capmatinib (INC280) 聯(lián)合吉非替尼在EGFR敏感突變/cMET+NSCLC患者中一項單臂Ib/II期研究：II期臨床研究結(jié)果報告,Presented by: Yi-Long Wu. Abs 9020 ASCO 2016.,研究背景,cMET特異表達在TKI獲得性耐藥的NSCLC患者中占1525%。 INC280是高選擇性cMET抑制劑，其聯(lián)合EGFR-TKIs在EGFR敏感突變/ cMET+NSCLC患者中顯示了臨床前和初步臨床活性。 本研究是評估INC280 聯(lián)合吉非替尼在經(jīng)吉非替尼/厄羅替尼/阿法替尼治療進展后的EGFR敏感突變合并cMET+ NSCLC患者中Ib/II期臨床研究(NCT01610336)。 此次報告II期劑量擴展階段臨床研究數(shù)據(jù)。,Presented by: Yi-Long Wu. Abs 9020 ASCO 2016.,研究設(shè)計 Ib/II期、單臂、開放、多中心臨床研究,主要終點( II期 )：ORR 次要終點( II期 ) : OS、 DoR、PFS 、AE、PK,Presented by: Yi-Long Wu. Abs 9020 ASCO 2016.,Presented by:,患者主要入組標(biāo)準(zhǔn)： 年齡18歲 NSCLC EGFR+（exon19del/L858R，無T790M） 曾接受過EGFR TKI治療并有可測量的臨床獲益 耐藥后cMET+（免疫組化3+, 或免疫組化2+且基因拷貝數(shù)GCN 5） ECOG PS2 期望壽命3個月 截至2015年9月，該研究期擴大試驗共納入83名患者。期推薦劑量（RP2D）為INC280/400mg（BID）+吉非替尼/250mg（QD）。,基線特征,截止2016年3月1日，75患者停止治療，中位暴露時間為16.7 周,研究結(jié)果,總?cè)巳篛RR 31%；DCR 81% ；mPFS 24周 (95%CI 16.624.1) GCN 6 亞組, ORR 50% DCR 84%；各亞組mPFS未成熟,研究結(jié)果,靶病灶體積的最佳緩解百分比,總體人群,各GCN亞組,不良事件,所有級別最常見AE(25)有：惡心、外周水腫、低蛋白血癥、食欲減低 最常見藥物相關(guān)AE是惡心，發(fā)生率27% 最常見3/4 AE有淀粉酶升高和脂肪酶升高，發(fā)生率均為6 最常見藥物相關(guān)3/4 AE是脂肪酶升高 SAE發(fā)生率29%； SAE中發(fā)生率（3）較高的有：肺部感染（4級），肺炎（3級），肺栓塞（3級） 藥物相關(guān)SAE發(fā)生率7%,研究結(jié)論,capmatinib (INC280) 聯(lián)合吉非替尼顯示初步臨床療效，尤其是在高水平cMET擴增腫瘤患者中 capmatinib 聯(lián)合吉非替尼耐受性良好 所有級別、3/4級藥物相關(guān)不良反應(yīng)中最多見的分別是惡心、脂肪酶升高 capmatinib 與吉非替尼之間未報告有藥物相互作用 capmatinib 聯(lián)合吉非替尼為EGFR突變合并cMET+ NSCLC患者提供了新的治療思路,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, NC Clinical 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,4 Mark A. Socinski,5Jared Weiss,6 Gregory J. Riely,1 Maria Winter,7 Sherry 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), confirmed Stable disease (SD): includes 4 unconfirmed PRs,*,*,* Stable disease and 0% change from baseline,Presented by: Alexander Drilon MD,Antitumor Activity,Partial response (PR), confirmed Stable 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）患者僅有MET 14外顯子突變，與MET擴增不重疊，提示MET 14外顯子突變與MET擴增在大部分病例中是兩個相互獨立、可分別使用藥物治療的生物標(biāo)志物。,Presented by: Alexander Drilon MD,Abstract：9021 攜帶MET外顯子14改變的不同組織學(xué)類型的298例肺癌基因組綜合分析,Sai-Hong Ignatius Ou.et al. ASCO 2016 Abstract 9021.,背景,最近MET基因外顯子14跳躍缺失突變（METex14）成為MET抑制劑的潛在靶點。 然而，大樣本的攜帶METex14改變的肺癌患者研究尚未見報道。,Sai-Hong Ignatius Ou.et al. ASCO 2016 Abstract 9021.,方法,從236個癌癥相關(guān)基因和19個基因的47內(nèi)含子中采用雜交捕獲的技術(shù)得到至少3769個外顯子，這些外顯子在癌癥通常是重排的 樣品統(tǒng)一進行前瞻性高通量測序（平均820X），并作為常規(guī)的臨床工作的一部分（2012年8月 - 2015年11月） 患者樣品通過基因組改變（GAs）評價，包括堿基對取代，插入/刪除，拷貝數(shù)變化和重排進行評價。然后這些GAs再進行人工檢查，以找出那些可能影響到MET14號外顯子剪接的，或者整個刪除這個外顯子 比較關(guān)系用Mann-Whitney U檢驗進行了檢驗;使用Pearson卡方檢驗與Yates連續(xù)性校正檢查明確關(guān)系,Sai-Hong Ignatius Ou.et al. ASCO 2016 Abstract 9021.,方法,1)DNA/RNA 提取,2)分子捕獲技術(shù),3)分析技術(shù),4)臨床報告,Sai-Hong Ignatius Ou.et al. ASCO 2016 Abstract 9021.,基線特征,組織學(xué)類型N（%）：腺癌 205（68.8）腺鱗癌8（2.7）鱗癌25（8.4）大細(xì)胞癌2（0.7）肉瘤8（2.7）小細(xì)胞1（0.3）NSCLC NOS 49（16.4）,Sai-Hong Ignatius Ou.et al. ASCO 2016 Abstract 9021.,基線特征,剪接供體(Splice donor site, SD)、剪接受體(Splice acceptor site, SA)，non-c：non-coding非編碼;indel; insertion and deletion，插入缺失；sub:substitution替換,Sai-Hong Ignatius Ou.et al. ASCO 2016 Abstract 9021.,基線特征,Sai-Hong Ignatius Ou.et al. ASCO 2016 Abstract 9021.,根據(jù)患者臨床和分子特征比較METex14 NSCLC有或無并發(fā)MET擴增,