2019年ASCO肺癌靶向治疗新进展-6.12.ppt

1、2019年ASCO肺癌靶向治疗新进展新靶点、新药物、新策略,主要内容,EGFR： 克服耐药：JNJ-372，U3-1402 延缓耐药： RELAY研究，化疗+TKI，9291+A EGFR-20插入： JNJ-372， TAK788 K-RAS：AMG510，曲美替尼+多西他赛 ALK：J-ALEX更新，Brigatinib 后线 ROS1：Repotrectinib C-met：Tepotinib，Capmatinib RET：BLU-667 Her-2：吡咯替尼 B-raf: NTRKs：,NCCN指南推荐检测八个基因+K-RAS,主要内容,EGFR： 克服耐药：JNJ-372，U3-14

2、02， 延缓耐药： RELAY研究，化疗+TKI，9291+A EGFR-20插入： JNJ-372， TAK788 K-RAS：AMG510，曲美替尼+多西他赛 ALK：J-ALEX更新，Brigatinib 后线 ROS1：Repotrectinib C-met：Tepotinib，Capmatinib RET：BLU-667 Her-2：吡咯替尼 B-raf: NTRKs：,NCCN指南推荐检测八个基因+K-RAS,PFS（月）,埃克替尼,10项TKI vs. CT的RCT奠定了EGFR-TKI为EGFR+的NSCLC一线标准治疗的地位,Chen G, et al. Ann Oncol

3、2013;24:161522; Gefitinib Summary of Product Characteristics 2010; Han JY, et al. J Clin Oncol.2012;30:11228; Maemondo M, et al. N Engl J Med.2010;362:23808; Mok T, et al. N Engl J Med.2009; 361:94757; Mitsudomi T, et al. Lancet Oncol.2010;11:1218; Rosell R, et al.Lancet Oncol.2012;13:23946; Sequist

4、 LV, et al. J Clin Oncol.2013;31:332734; Soria JC, et al. N Engl J Med. 2018 Jan 11;378(2):113-125. Wu YL, et al. Lancet Oncol.2014;15:21322; Wu YL, et al. Ann Onc.2015; Ann Oncol.2015; 26:1883-9; Zhou C, et al. Lancet Oncol.2011; 8:73542.,阿法替尼,二代 vs. 一代TKI,27%,16%,16%,8%,0,42,36,30,24,18,12,6,0.0,0

5、.2,0.4,0.6,0.8,1.0,PFS概率,月,PFS率 30.6% vs 9.6%,LUX-Lung 7,ARCHER-1050,二代 vs. 一代TKI,J Clin Oncol.2018 Jun 4,第一个OS阳性结果,阿法替尼 vs 吉非替尼 达克替尼 vs 吉非替尼,Paz-Ares et al. Ann Oncol 2017,PFS,WHO体力状态为0 / 1,*日本为年龄20 ； #中心实验室进行敏感性评估； cobas EGFR 突变检测(Roche Molecular Systems); Sites在研究中心启动前选择吉非替尼或厄洛替尼作为唯一对照药的研究中心； 18个

6、月后每12周一次；CNS，中枢神经系统；EGFR，表皮生长因子受体；NSCLC，非小细胞肺癌；PFS，无进展期； p.o，口服； RECIST 1.1，1.1版实体瘤疗效评价标准；qd，每日一次；SoC，标准治疗；FLAURA数据截止日期：2017年6月12日；NCT02296125 Ramalingam SS, et al. 2017 ESMO Abstract LBA2.,本研究有90%的把握度以双侧5%的水平检出0.71的风险比(代表中位PFS从10个月延长至14.1个月),次要终点：客观缓解率、缓解持续时间、疾病控制率、缓解深度、总生存期、患者自评结果、安全性, 按突变状态(Del 1

7、9/ L858R) 和种族(亚裔/非亚裔)分层,奥希替尼 (80 mg p.o. qd) (n=279) EGFR-TKI SoC; 吉非替尼 (250 mg p.o. qd) 或厄洛替尼 (150 mg p.o. qd) (n=277),每6周进行一次RECIST 1.1评估， 直至出现客观疾病进展 SoC组患者允许交叉， 如果中心实验室确认疾病 进展且T790M阳性，患者 可接受奥希替尼开放治疗,FLAURA双盲研究设计 局部晚期或转移性NSCLC的患者 关键入选标准 18岁* R Del 19/ L858R(当地# 或中心实验室EGFR检测) 既往未接受全身性抗癌/ EGFR-TKI 治

8、疗 允许稳定性CNS 转移 1:1 主要终点：研究者评估的PFS (基于RECIST 1.1),ORR (95%Cl),奥希替尼 (n=279) 80% (75,85),SoC (n=277) 76% (70,81),OR# (95%Cl),1.28 (0.85,1.93); P=0.2335,CR, n(%) PR, n(%) SD6周, n(%) 进展, n(%) 不可评估, n(%),7 (3) 216 (77) 47 (17) 3 (1) 6 (2),4 (1) 206 (74) 46 (17) 14 (5) 7 (3),仍持续缓解估值, (95%Cl) 12个月 18个月 中位DOR

9、 (月),64% (58, 71) 49% (41, 56) 17.2 (N=223),37% (31, 44) 19% (13, 26) 8.5 (N=210),0,15,18,21,24,27,12 时间 (月),0.2 0.0,0.8 0.6 0.4,1.0,奥希替尼(n=279) 标准治疗(SoC)(n=277),中位PFS, 月 (95% Cl) 18.9 (15.2， 21.4) 10.2 (9.6, 11.1),HR 0.46 (95% Cl 0.37, 0.57) P0.0001 3 6 9,三代 vs. 一代TKI,OS仍不成熟,三代同堂,EGFR-TKIs耐药：,Camid

10、ge, et al. Nat Rev Clin Oncol.2014Aug;11(8):473-81.,FLAURA研究: 奥希替尼 (n=91)*的获得性耐药机制,解决治疗瓶颈的策略,1、克服耐药 2、延缓耐药,克服T790M介导的耐药：9291,第三代TKI直接一线使用,克服耐药（T790M）,1、N Engl J Med. 2017 Feb 16;376(7):629-640； 2、N Engl J Med. 2018 Jan 11;378(2):113-125,Clinical trials - EGFR + cMET inhibitors the world of TKIs,Pres

11、ented By Jessica Bauman at 2019 ASCO Annual Meeting,克服c-met介导耐药的临床研究,新药： EGFR-cMET双特异性抗体JNJ-372,新药： EGFR-cMET双特异性抗体JNJ-372,作用机制,研究设计,入组患者特征,Slide 12,JNJ-372用于C797S、20ins、MET扩增患者有效,32/108 (30%),Post 3GTKI:RR 28%exon20ins:RR 30%,克服第三代TKI耐药： JNJ-372,C797S、c-met扩增、其他机制均有一定有效率,ORR=28%，N=58,Safety and pre

12、liminary antitumor activity of U3-1402, a HER3-targeted antibody drug conjugate, in EGFR TKI-resistant, EGFRm NSCLC,Presented By Pasi Janne at 2019 ASCO Annual Meeting,克服耐药：新药U3-1402,Slide 4,Presented By Pasi Janne at 2019 ASCO Annual Meeting,Her-3广泛表达于EGFR突变细胞,Slide 5,Presented By Pasi Janne at 201

13、9 ASCO Annual Meeting,药物设计,Slide 11,Presented By Pasi Janne at 2019 ASCO Annual Meeting,研究设计,Slide 15,Presented By Pasi Janne at 2019 ASCO Annual Meeting,ORR=31%,疗效数据,解决治疗瓶颈的策略,1、克服耐药 2、延缓耐药,延缓耐药：A+T,JO25567：厄洛替尼 贝伐珠单抗（II期） NEJ026：厄洛替尼 贝伐珠单抗（III期）,2018-ASCO,RELAY: A multicenter, double-blind, random

14、ized Phase 3 study of erlotinib in combination with ramucirumab or placebo in previously untreated patients with epidermal growth factor receptor mutation-positive metastatic non-small cell lung cancer,Presented By Kazuhiko Nakagawa at 2019 ASCO Annual Meeting,延缓耐药：A+T,1. Garon EB et al. Clin Lung C

15、ancer 2017; 2. Reck M et al. Clin Lung Cancer 2018 Presented By Kazuhiko Nakagawa at 2019 ASCO Annual Meeting,RELAY研究：厄洛替尼联合雷莫芦单抗用于初治EGFR M+ NSCLC患者的多中心、双盲、随机对照3期研究,Slide 8,Presented By Kazuhiko Nakagawa at 2019 ASCO Annual Meeting,PFS数据,Slide 13,Presented By Kazuhiko Nakagawa at 2019 ASCO Annual Me

16、eting,T790M耐药占比,延缓耐药：9291+Avastin,ORR: 80% PFS: 18.4,N= 49,延缓耐药：化疗+TKIs,JMIT,Gefitinib versus gefitinib-pemetrexed-carboplatin in EGFR mutated lung cancer (Gef vs. Gef + C),Presented By Vanita Noronha at 2019 ASCO Annual Meeting,延缓耐药：化疗+TKI,研究设计,Presented By Vanita Noronha at 2019 ASCO Annual Meetin

17、g,J Clin Oncol 37, 2019 (suppl; abstr 9001),疗效数据,NSCLC中的EGFR突变,1. Mitsudomi et al., Cancer Science, 2007 2. Nature Review 2007, 7:169,EGFR-20外显子插入突变: EGFR第一、二代TKIs均不敏感,EGFR Exon 20 Insertions 肺癌： EGFR和cMET双特异性抗体JNJ-372,ORR= 30%, N=27,Lung Cancer 127 (2019) 146152,C225增加阿法替尼、AZD9291的疗效,新方案：阿法替尼+C225,

18、J Thorac Oncol. 2018,3/4 PR,研究方案,IIIB或IV晚期NSCLC EGFR-20外显子插入 ECOG PS 0-1 一线标准治疗后,A组: Afatinib: 30mg或AZD9291 C225：250mg/m2/两周,B组： Afatinib: 30mg或AZD9291 C225：500mg/m2/两周,主要研究终点： safety 次要终点： ORR，PFS，OS, Bio-markers,C组： Afatinib: 40mg或AZD9291 C225：250mg/m2/两周,D组： Afatinib: 40mg或AZD9291 C225：500mg/m2/两

19、周,N=3-12 N=3-12 N=3-12 N=3-12,Ib,II,IIIB或IV晚期NSCLC EGFR-20外显子插入 ECOG PS 0-1 一线标准治疗后,A or B or C or D (Best) , N=60例,主要研究终点： ORR 次要终点： PFS，OS, Bio-markers,注册临床研究,Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions,Presented By Pasi Janne at 2019 ASCO Annual Meeting,EGFR Exon 20 Insert

20、ions 肺癌新药：TAK788,TAK-788 Antitumor Activity in Patients With EGFR Exon 20 Insertions,Presented By Pasi Janne at 2019 ASCO Annual Meeting,有效率：ORR=43%,TAK-788 Antitumor Activity in Patients With EGFR Exon 20 Insertions,Presented By Pasi Janne at 2019 ASCO Annual Meeting,不用类型均有效,EGFR阳性肺癌新进展： 现状：三代同堂 未来

21、：克服耐药 (JNJ-372，U3-1402 联合、IO+C) 延缓耐药（A+T、化疗联合TKIs） EGFR-20插入：波奇替尼、TAK-788、 JNJ-372, C255+afatinib,主要内容,EGFR： 克服耐药：JNJ-372，U3-1402， 延缓耐药： RELAY研究，化疗+TKI，9291+A EGFR-20插入： JNJ-372， TAK788 K-RAS：AMG510，曲美替尼+多西他赛 ALK：J-ALEX更新，Brigatinib 后线 ROS1：Repotrectinib C-met：Tepotinib，Capmatinib RET：BLU-667 Her-2：

22、吡咯替尼 B-raf: NTRKs：,NCCN指南推荐检测八个基因+K-RAS,Phase 1 Study Evaluating the Safety, Tolerability, Pharmacokinetics (PK) and Efficacy of AMG 510, a Novel Small Molecule KRASG12C Inhibitor, in Advanced Solid Tumors,Presented By Marwan Fakih at 2019 ASCO Annual Meeting,K-RAS 新药：AMG 510,AMG 510 is a First in C

23、lass KRASG12C Inhibitor,Presented By Marwan Fakih at 2019 ASCO Annual Meeting,K-RAS 新药：AMG 510,AMG 510 First in Human Study Design,Presented By Marwan Fakih at 2019 ASCO Annual Meeting,研究设计,Patient Incidence of Common (10%) and Serious Treatment Emergent Adverse Events (TEAE),Presented By Marwan Fak

24、ih at 2019 ASCO Annual Meeting,安全性,NSCLC: Best Tumor Response* (n=10),Presented By Marwan Fakih at 2019 ASCO Annual Meeting,ORR=50%,NSCLC疗效数据,打响了肺癌K-ras单药靶向治疗的第一枪,CRC and Other Solid Tumors: Best Tumor Response* (n=19),Presented By Marwan Fakih at 2019 ASCO Annual Meeting,肠癌及其他瘤种疗效数据,Duration of Tre

25、atment by Tumor Types and Responses (n=29),Presented By Marwan Fakih at 2019 ASCO Annual Meeting,持续治疗时间,ORR=33%,ORR=26%,ORR=37%,(n=54),(n=19),(n=35),主要内容,EGFR： 克服耐药：JNJ-372，U3-1402， 延缓耐药： RELAY研究，化疗+TKI，9291+A EGFR-20插入： JNJ-372， TAK788 K-RAS：AMG510，曲美替尼+多西他赛 ALK：J-ALEX更新，Brigatinib 后线 ROS1：Repotrec

26、tinib C-met：Tepotinib，Capmatinib RET：BLU-667 Her-2：吡咯替尼 B-raf: NTRKs：,NCCN指南推荐检测八个基因+K-RAS,阿来替尼在NSCLC的PFS创造了一个新的高峰,34.8,（n=207）,J-ALAX研究数据更新：PFS：34.1 M,Lancet 2017; 390: 2939,2019ASCO-9092,Brigatinib 后线疗效数据,至少一个二代ALK抑制剂后 接受至少两个ALK抑制剂后,ORR=40%,ORR=50%,PFS=6.4M,PFS=6.6M,Abstract ID：9027,Abstract ID：90

27、45,主要内容,EGFR： 克服耐药：JNJ-372，U3-1402， 延缓耐药： RELAY研究，化疗+TKI，9291+A EGFR-20插入： JNJ-372， TAK788 K-RAS：AMG510，曲美替尼+多西他赛 ALK：J-ALEX更新，Brigatinib 后线 ROS1：Repotrectinib C-met：Tepotinib，Capmatinib RET：BLU-667 Her-2：吡咯替尼 B-raf: NTRKs：,NCCN指南推荐检测八个基因+K-RAS,ROS1 inhibitors in TKI naive patients,Presented By Benj

28、amin Besse at 2019 ASCO Annual Meeting,（洛普替尼）,（恩曲替尼）,ROS1 inhibitors in TKI pretreated patients,Presented By Benjamin Besse at 2019 ASCO Annual Meeting,ROS1 inhibitors,Presented By Benjamin Besse at 2019 ASCO Annual Meeting,主要内容,EGFR： 克服耐药：JNJ-372，U3-1402， 延缓耐药： RELAY研究，化疗+TKI，9291+A EGFR-20插入： JNJ-

29、372， TAK788 K-RAS：AMG510，曲美替尼+多西他赛 ALK：J-ALEX更新，Brigatinib 后线 ROS1：Repotrectinib C-met：Tepotinib，Capmatinib RET：BLU-667 Her-2：吡咯替尼 B-raf: NTRKs：,NCCN指南推荐检测八个基因+K-RAS,Paik Cancer Discovery 2015 * Tong - Clin Cancer Res 2016. Drilon A et al, J Thoracic Oncol, 2016.,C-met异常肺癌,C-met异常肺癌：第1类MET抑制剂,Cui JJ

30、, et al, J Med Chem. 2011 Sep 22;54(18):6342-63; Bladt F, et al, Clin Cancer Res. 2013 Jun 1;19(11):2941-51.,(INC280),（特泊替尼）,C-met扩增肺癌：克唑替尼、Capmatinib,C-met-14skipping肺癌：克唑替尼,Capmatinib in METex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 st

31、udy,Presented By Juergen Wolf at 2019 ASCO Annual Meeting,GEOMETRY mono-1: A phase II trial of capmatinib in patients with advanced NSCLC harboring MET exon14 skipping mutation,Presented By Juergen Wolf at 2019 ASCO Annual Meeting,Best overall response (pretreated cohort 4),Presented By Juergen Wolf

32、 at 2019 ASCO Annual Meeting,Best overall response (treatment naive cohort 5b),Presented By Juergen Wolf at 2019 ASCO Annual Meeting,Tumor shrinkage per BIRC,Presented By Juergen Wolf at 2019 ASCO Annual Meeting,Progression-free survival per BIRC,Presented By Juergen Wolf at 2019 ASCO Annual Meeting

33、,Conclusions,Presented By Juergen Wolf at 2019 ASCO Annual Meeting,反应率：54%;7/13；4例CR,Phase II study of tepotinib in NSCLC patients with METex14 mutations,Presented By Paul Paik at 2019 ASCO Annual Meeting,VISION study design,Presented By Paul Paik at 2019 ASCO Annual Meeting,研究设计,Efficacy: Best over

34、all response (IRC/Investigator),Presented By Paul Paik at 2019 ASCO Annual Meeting,客观有效率,Efficacy: Tumor shrinkage by line of therapy,Presented By Paul Paik at 2019 ASCO Annual Meeting,疗效数据,Efficacy: Progression-free survival,Presented By Paul Paik at 2019 ASCO Annual Meeting,PFS数据,主要内容,EGFR： 克服耐药：J

35、NJ-372，U3-1402， 延缓耐药： RELAY研究，化疗+TKI，9291+A EGFR-20插入： JNJ-372， TAK788 K-RAS：AMG510，曲美替尼+多西他赛 ALK：J-ALEX更新，Brigatinib 后线 ROS1：Repotrectinib C-met：Tepotinib，Capmatinib RET：BLU-667 Her-2：吡咯替尼 B-raf: NTRKs：,NCCN指南推荐检测八个基因+K-RAS,NATURE REVIEWS | CLINICAL ONCOLOGY VOLUME 15 | MARCH 2018 | 151,RET阳性肺癌：凡德他尼、卡博替尼、LOXO-292,BLU-667 Demonstrates Substantial Antitumor Activity in RET Fusion+ Advanced NSCLC,Presented By Justin Gainor at 2019 ASCO Annual Meeting,RET融合肺癌：BLU-667,ORR=71%,Drilon