1、1晚期NSCLC分子靶向药物最新进展2NSCLC治疗发展的里程碑Gefitinib approval for EGFR-mutant NSCLCCrizotinib approval for ALK+NSLCLEML4-ALK translocation discovered in NSCLC Identification of EGFR mutations in patients responsive to gefitinib2007201120042009Nat Rev Clin Oncol 2015;12:511-26 20153肺癌的分子分型和靶向治疗的地位ALK:Crizotinib
2、,Ceritinib,Alectinib,AP26113,PF-06463922EGFR:Gefitinib,Erlotinib,Icotinib,Afatinib,DacomitinibROS1:CrizotinibRET:CabozantinibMET:CrizotinibBRAF:DabrafenibHER2:Dacomitinib,AfatinibKRAS:SelumetinibAdenocarcinomaSquamous cell carcinoma_ CFDA approvalASCO 2014,Education BookLancet Oncol 2011;12:175-804W
3、CLC 2015 NSCLC个体化治疗新进展Total Presentations of WCLC 2015:2499 NSCLC基因组学研究包括个体间和瘤内异质性 ALK/EGFR TKI一线治疗的优化 TKIs获得性耐药的治疗策略 ALK/EGFR+NSCLC脑转移的治疗 NSCLC治疗新靶点5EGFR+NSCLC基因组学图谱和TKI耐药新机制 9个EGFR+NSCLC手术后标本，分成47份；30份EGFR+NSCLC耐药后活检标本，来自25个患者 全外显子测序（正常组织配对）和转录组测序6突变特征 在没有用过EGFR TKI的手术标本，所有区域均检测到EGFR突变，EGFR突变为干突变，
4、均没有测到T790M突变 TKI耐药后突变负荷增加，突变负荷与年龄，吸烟，及APOBEC蛋白表达相关7耐药突变图谱 TKI耐药突变呈异质性，多种耐药相关的突变共存 TKI耐药图谱表明在原发性耐药，在治疗开始前即存在多种driver干突变8结论 未使用过TKI的东亚EGFR+患者存在基因组学等级结构EGFR突变是干突变突变负荷低亚克隆的多样性高 TKI耐药患者突变负荷增加与吸烟及APOBEC突变图谱类似 多种TKI耐药机制共存如MED12改变可能调节亚克隆耐药原发性耐药者存在多种driver干突变9WCLC 2015 NSCLC个体化治疗新进展Total Presentations of WCL
5、C 2015:2499 NSCLC基因组学研究包括个体间和瘤内异质性 ALK/EGFR TKI一线治疗的优化 TKIs获得性耐药的治疗策略 ALK/EGFR+NSCLC脑转移的治疗 NSCLC治疗新靶点10JMIT研究：吉非替尼与培美曲塞联合的一线治疗11吉非替尼与培美曲塞联合延长吉非替尼单药治疗的PFS 吉非替尼与培美曲塞联合一线治疗与吉非替尼单药相比，明显延长PFS 无论是19外显子缺失还是21外显子L858R点突变，吉非替尼联合培美曲塞均有PFS的获益12WCLC 2015 NSCLC个体化治疗新进展Total Presentations of WCLC 2015:2499 NSCLC基
6、因组学研究包括个体间和瘤内异质性 ALK/EGFR TKI一线治疗的优化 TKIs获得性耐药的治疗策略 ALK/EGFR+NSCLC脑转移的治疗 NSCLC治疗新靶点13三代ALK/ROS1 TKI：lorlatinib(PF-06463922)在晚期ALK/ROS1 NSCLC中的疗效和安全性14ORRLorlatinib对ALK G1202R突变的疗效 15颅内病灶的疗效 Lorlatinib在ALK+和ROS1+NSCLC中显示出了抗肿瘤活性，尤其是这些患者大部分具有脑转移及经过1 TKI治疗 显著的脑转移的抗肿瘤活性表明lorlatinib能够透过血脑屏障，达到 有效的抗肿瘤活性16P
7、F-06463922 Is Active Against All Known ALK and ROS1 Resistance Mutations1,*Based on results in BaF3 cell line 1.Zou HY,et al.AACR-NCI 2013,poster A27717IMPRESS亚组分析T790M亚组分析18T790M亚组PFST790M(-)T790M(+)19T790M亚组OS41%maturity,HR(95%CI)=2.16(1.26,3.82);P=0.006723%maturity,HR(95%CI)=0.83(0.36,1.85);P=0.6
8、644T790M(+)T790M(-)RECIST标准进展时，对于T790M突变阳性的患者，吉非替尼不应该与二线化疗联合使用 RECIST标准进展时，对于T790M突变阴性的患者，吉非替尼继续使用，联合化疗的获益需要进一步验证20WCLC 2015 NSCLC个体化治疗新进展Total Presentations of WCLC 2015:2499 NSCLC基因组学研究包括个体间和瘤内异质性 ALK/EGFR TKI一线治疗的优化 TKIs获得性耐药的治疗策略 ALK/EGFR+NSCLC脑转移的治疗 NSCLC治疗新靶点21PROFILE 1014脑转移亚组分析：克唑替尼一线治疗与化疗比较
9、的颅内疗效分析Key entry criteriaALK-positive by central FISH testinga Locally advanced,recurrent,or metastatic non-squamous NSCLC No prior systemic treatment for advanced disease ECOG PS 02 Measurable disease Stableb treated brain metastases allowedEndpoints Primary PFS(RECIST 1.1,independent radiologic re
10、view IRR)Secondary ORR OS Intracranial TTPe Safety Patient-reported outcomesCrossover to crizotinib permitted after progressiond N=343RANDOMIZEcCrizotinib 250 mg BID PO,continuous dosing(n=172)Pemetrexed 500 mg/m2+cisplatin 75 mg/m2 or carboplatin AUC 56 q3w for 6 cycles(n=171)Intracranial efficacy
11、was prospectively evaluated in the ITT population and patients with and without brain metastases at baselineeAbstract 123822Baseline Characteristics of Patients With/without Brain Metastases at BaselineaCarc.,carcinoma;aby IRR;bpreviously treated per protocol,although this criterion was not fulfille
12、d in all cases cAt screening;data for 1 patient missing for crizotinibBrain metastasesb presentBrain metastases absentCharacteristicCrizotinib(n=39)Chemo(n=40)Crizotinib(n=132)Chemo(n=131)Age,yearsMedian(range)48(2970)51(2576)53(2276)56(1978)Sex,n(%)Male20(51)9(23)47(36)54(41)Race,n(%)CaucasianAsian
13、Other20(51)17(44)2(5)19(48)18(45)3(8)70(53)60(45)2(2)66(50)62(47)3(2)Smoking,n(%)Never smokedEx-smokerCurrent smoker23(59)13(33)3(8)28(70)12(30)083(63)43(33)6(5)84(64)42(32)5(4)Histology,n(%)Adenocarc.Large cell carc.Adenosquamous carc.Other35(90)1(3)2(5)1(3)38(95)01(3)1(3)123(93)2(2)3(2)4(3)121(92)
14、8(6)02(2)ECOG PS,c n(%)0/1235(90)4(10)34(85)6(15)125(95)6(5)129(98)2(2)Time since first diagnosis,moMedian(range)2.4(036.0)2.4(1.274.4)1.2(0114.0)1.2(093.6)23Antitumor Activity PFS and ORRaaBy IRRbAt baselinecTwo-sided log-rank test(ITT population:stratified;patient subgroups with/without baseline b
15、rain metastases:unstratified)dCrizotinib vs.chemotherapyeTwo-sided Pearson 2 testITT populationBrain metastases presentbBrain metastases absentbCrizotinib(N=172)Chemo(N=171)Crizotinib(n=39)Chemo(n=40)Crizotinib(n=132)Chemo(n=131)Median PFS,mo(95%CI)10.9(8.313.9)7.0(6.88.2)9.0(6.815.0)4.0(1.56.8)11.1
16、(8.314.0)7.2(6.98.3)HR(95%CI)0.45(0.350.60)0.40(0.230.69)0.51(0.380.69)Pc0.0010.0010.001ORR,%(95%exact CI)74(6781)45(3753)77(6189)28(1544)74(6682)50(4259)Differenced(95%exact CI)29(2039)49(3069)24(1335)Pe0.0010.0010.00124Intracranial DCRa in Patients With Brain Metastases at BaselineDCR,disease cont
17、rol rate(%CR+PR+SD)aBy IRR;btwo-sided Pearson 2 test12 weeks24 weeksIntracranial DCR(95%exact CI;%)Difference:40%(95%CI:2159)P0.001bDifference:31%(95%CI:1152)P=0.006b10080604020025Intracranial TTPa in ITT PopulationCrizotinib(n=172)Chemotherapy(n=171)Events,n(%)25(15)26(15)Median,moNR17.8HR(95%CI)0.
18、60(0.341.05)Pb0.069NR,not reachedaTime from randomization to first documentation of intracranial tumor progression by IRR bTwo-sided log-rank testProbability of no progression(%)100806040200051015202530351721711191076539401421 3811000CrizotinibChemotherapy No.at riskTime(months)26Intracranial TTPa i
19、n Patients With/without Brain Metastases at BaselineBrain metastases presentBrain metastases absentCriz(n=39)Chemo(n=40)Events,n(%)9(23)12(30)Median,mo15.712.5HR(95%CI)0.45(0.191.07)Pb0.063NR,not reachedaTime from randomization to first documentation of intracranial tumor progression by IRR bTwo-sid
20、ed log-rank testProbability of no progression(%)10080604020005101525353940CrizotinibChemotherapy No.at riskTime(months)26159773103020100000Probability of no progression(%)0132131CrizotinibChemotherapy No.at riskTime(months)93925632331120 37110001008060402005101525302035Criz(n=132)Chemo(n=131)Events,
21、n(%)16(12)14(11)Median,moNRNRHR(95%CI)0.69(0.331.45)Pb0.32327Duration of Treatment Before/After Intracranial PD in Patients Randomized to CrizotinibTreatment duration(weeks)070 80 9010010090807060504030201060 50 403020 10*BM at baselineNo BM at baselineRadiotherapy after intracranial PDOn treatment
22、at data cutoffHad intracranial PD in existing lesion*Duration of treatment beyond intracranial PD:a median 20.4 weeks(range:3.384.4)aAmong the 22 patients receiving crizotinib for 3 weeks beyond intracranial PD 28结论无论有无脑转移，对于ALK阳性NSCLC，克唑替尼一线治疗优于标准化疗。-克唑替尼12周和24周DCR优于化疗-克唑替尼在颅内TTP方面，显示出数值上的优势 克唑替尼是A
23、LK阳性NSCLC的标准治疗，包括脑转移患者29WCLC 2015 NSCLC个体化治疗新进展Total Presentations of WCLC 2015:2499 NSCLC基因组学研究包括个体间和瘤内异质性 ALK/EGFR TKI一线治疗的优化 TKIs获得性耐药的治疗策略 ALK/EGFR+NSCLC脑转移的治疗 NSCLC治疗新靶点30MET 14外显子跳跃剪接突变发生率和患者的临床特征 2014-2015年间，678例非鳞癌测序，27例（4%）MET 14外显子跳跃剪接突变，有3例（11%）同时有MET扩增 大部分为腺癌 吸烟史不定31对MET抑制剂的反应病例5：对克唑替尼反应
24、病例：对卡博替尼耐药后，克唑替尼有效 MET 14外显子跳跃剪接突变是一种新的driver突变，对MET抑制剂显示有反应 这是除了EGFR和ALK突变外，发生率最高的突变 对MET抑制剂有反应的患者，常常不伴有MET扩增，对这类患者的临床研究正在进行中（NCT00585195）32WCLC 2015的启示之一：以biomarker筛选人群的重要性Co-Primary endpoint:PFS in EGFR FISH+patientsOS in entire populationSecondary:OS/PFS by bevacizumab appropriate/inappropriateS
25、afety/toxicity by treatment arm Exploratory:OS in entire study and FISH+SCCA patients33入组病例34无论是全人群还是EGFR FISH+人群都无OS和PFS的获益Entire studyEGFR FISH+35无论是贝伐适用于人群还是不适用人群，都无OS获益36EGFR FISH+鳞癌OS获益 EGFR FISH+对于肺鳞癌，可能是一个有意义的分子靶点 EGFR H score和KRAS状态的分析正在进行SWOG S0819更提示：在肺癌精准治疗时代，以biomarker筛选人群对于靶向治疗的临床研究的必要性！37总结 靶向治疗仍是目前的热点，一代EGFR TKI治疗的优化，后续ALK TKI的临床研究正在火热进行中 NSCLC基因组学及耐药机制的研究，对于预防耐药乃至耐药后的治疗策略意义深远
