SCO肺癌靶向治疗新进展

1、ASCO肺癌靶向治疗新进展新靶点、新药物、新策略12020/4/9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， TAK788K-RAS：AMG510，曲美替尼+多西他赛ALK：J-ALEX更新，Brigatinib 后线ROS1：RepotrectinibC-met：Tepotinib，CapmatinibRET：BLU-667Her-2：吡咯替尼B-raf: NTRKs：NCCN指南推荐检测八个基因+K-RAS42022/8/2主要内容EGFR： 克服耐药：JNJ-372，U3-1

2、402， 延缓耐药： RELAY研究，化疗+TKI，9291+A EGFR-20插入： JNJ-372， TAK788K-RAS：AMG510，曲美替尼+多西他赛ALK：J-ALEX更新，Brigatinib 后线ROS1：RepotrectinibC-met：Tepotinib，CapmatinibRET：BLU-667Her-2：吡咯替尼B-raf: NTRKs：NCCN指南推荐检测八个基因+K-RAS52022/8/2厄洛替尼吉非替尼含铂类化疗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.

3、 Ann Oncol 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;13:239

4、46; Sequist 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62022/8/2二代 vs. 一代TKI无进展生存率（%）100806040200时间（月

5、）03691215182124273033263942454851阿法替尼（n=160）吉非替尼（n=159）中位数，月11.010.9HR（95% CI）p值0.74（0.57-0.95）0.017827%16%16%8%达可替尼（N=227）吉非替尼（N=225）中位数，月14.79.2HR（95% CI）p值0.59 (0.47 - 0.74)p0.0001042363024181260.00.20.40.60.81.0PFS概率月删失PFS率30.6% vs 9.6%LUX-Lung 7ARCHER-105072022/8/2二代 vs. 一代TKIJ Clin Oncol.2018

6、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 201782022/8/2PFSWHO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；So

7、C，标准治疗；FLAURA数据截止日期：2017年6月12日；NCT02296125Ramalingam 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 19/ 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 (150mg p.o. qd

8、) (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

9、,1.93); P=0.2335CR, 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 (月)64% (58, 71)49% (41, 56)17.2(N=223)37% (31, 44)19% (13, 26)8.5(N=210)0151821242712时间 (月)0.20.00.80.60.41.0奥希替尼(n=279)标准治疗(SoC)(n=277)中位PFS, 月 (95%

10、Cl)18.9 (15.2， 21.4)10.2 (9.6, 11.1)HR 0.46(95% Cl 0.37, 0.57)P0.00013 6 9三代 vs. 一代TKIOS仍不成熟92020/4/9三代同堂102022/8/2EGFR-TKIs耐药：Camidge, 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112022/8/2解决治疗瓶颈的策略1、克服耐药2、延缓耐药122022/8/2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 En

11、gl J Med. 2017 Feb 16;376(7):629-640； 2、N Engl J Med. 2018 Jan 11;378(2):113-125132022/8/2Clinical trials - EGFR + cMET inhibitors the world of TKIsPresented 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-372162022/8/2作用机制172022/8/2研究设计入

12、组患者特征Slide 12JNJ-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-372C797S、c-met扩增、其他机制均有一定有效率ORR=28%，N=58Safety and preliminary antitumor activity of U3-1402, a HER3-targeted antibody drug conjugate, in EGFR TKI-resistant, EGFRm NSCLC Presented By Pasi Janne a

13、t 2019 ASCO Annual Meeting克服耐药：新药U3-1402Slide 4Presented By Pasi Janne at 2019 ASCO Annual MeetingHer-3广泛表达于EGFR突变细胞Slide 5Presented By Pasi Janne at 2019 ASCO Annual Meeting药物设计Slide 11Presented By Pasi Janne at 2019 ASCO Annual Meeting研究设计Slide 15Presented By Pasi Janne at 2019 ASCO Annual Meeting

14、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272022/8/2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-ASCO282022/8/2RELAY: A multicenter, double-blind, randomized Phase 3 study of erlotinib in combination with ramucirumab or placebo in previously untreated patients with epidermal growth factor rec

15、eptor mutation-positive metastatic non-small cell lung cancerPresented By Kazuhiko Nakagawa at 2019 ASCO Annual Meeting延缓耐药：A+T1. Garon EB et al. Clin Lung Cancer 2017; 2. Reck M et al. Clin Lung Cancer 2018 Presented By Kazuhiko Nakagawa at 2019 ASCO Annual MeetingRELAY研究：厄洛替尼联合雷莫芦单抗用于初治EGFR M+ NSC

16、LC患者的多中心、双盲、随机对照3期研究Slide 8Presented By Kazuhiko Nakagawa at 2019 ASCO Annual MeetingPFS数据Slide 13Presented By Kazuhiko Nakagawa at 2019 ASCO Annual MeetingT790M耐药占比延缓耐药：9291+AvastinORR: 80%PFS: 18.4N= 49延缓耐药：化疗+TKIsJMIT342022/8/2Gefitinib versus gefitinib-pemetrexed-carboplatin in EGFR mutated lung

17、 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 MeetingJ Clin Oncol 37, 2019 (suppl; abstr 9001)疗效数据NSCLC中的EGFR突变EGF结合 EGF结合TM 酪氨酸激酶区 外显子2 5 7 13 16 17 18-21 22-24 28688728729761762823824875外显子18外显子19外显子20

18、外显子21Ex19DelL858RG719XL861QEx20 Ins388/2/2022EGFR-20外显子插入突变: EGFR第一、二代TKIs均不敏感398/2/2022402022/8/2EGFR Exon 20 Insertions 肺癌： EGFR和cMET双特异性抗体JNJ-372 ORR= 30%, N=27412022/8/2Lung Cancer 127 (2019) 146152C225增加阿法替尼、AZD9291的疗效422022/8/2新方案：阿法替尼+C225J Thorac Oncol. 20183/4 PR438/2/2022研究方案IIIB或IV晚期NSCLC

19、 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-markersC组： Afatinib: 40mg或AZD9291 C225：250mg/m2/两周D组： Afatinib: 40mg或AZD9291 C225：500mg/m2/两周N=3-12N=3-12N=3-12N=3-12Ib II IIIB或IV晚期NSCLC EGFR-20外显子插

20、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448/2/2022Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertionsPresented By Pasi Janne at 2019 ASCO Annual MeetingEGFR Exon 20 Insertions 肺癌新药：TAK788TAK-788 Antitumor Activity in Patients With EGF

21、R Exon 20 InsertionsPresented By Pasi Janne at 2019 ASCO Annual Meeting有效率：ORR=43%TAK-788 Antitumor Activity in Patients With EGFR Exon 20 InsertionsPresented 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：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-

22、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， TAK788K-RAS：AMG510，曲美替尼+多西他赛ALK：J-ALEX更新，Brigatinib 后线ROS1：RepotrectinibC-met：Tepotinib，CapmatinibRET：BLU-667Her-2：吡咯替尼B-raf: NTRKs：NCCN指南推荐检测八个基因+K-RAS492022/8/2Phase 1 Study Evaluating the S

23、afety, 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 MeetingK-RAS 新药：AMG 510502022/8/2AMG 510 is a First in Class KRASG12C InhibitorPresented By Marwan Fakih at 2019 ASCO

24、Annual MeetingK-RAS 新药：AMG 510AMG 510 First in Human Study DesignPresented 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 Fakih at 2019 ASCO Annual Meeting安全性NSCLC: Best Tumor Response* (n=10)Pr

25、esented By Marwan Fakih at 2019 ASCO Annual MeetingORR=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 Treatment by Tumor Types and Responses (n=29)Presented By Marwan Fakih at 2019 ASC

26、O 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， TAK788K-RAS：AMG510，曲美替尼+多西他赛ALK：J-ALEX更新，Brigatinib 后线ROS1：RepotrectinibC-met：Tepotinib，CapmatinibRET：BLU-667Her-2：吡咯替尼B-raf: NTRKs：NCCN指南推荐检测八个基因+K-RAS582022/

27、8/2阿来替尼在NSCLC的PFS创造了一个新的高峰34.8592022/8/2阿来替尼 300mg BID每28天一个周期n=103克唑替尼 250mg BID每28天一个周期n=104R1:1IIIB/IV期 NSCLC经IHC、FISH 或 RT-PCR检测确诊为ALK+ 肿瘤未接受过化疗 或 接受过一线化疗未接受过ALK抑制剂治疗ECOG PS 02（n=207）J-ALAX研究数据更新：PFS：34.1 MLancet 2017; 390: 29392019ASCO-9092602022/8/2Brigatinib 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O

28、RR=40%ORR=50%PFS=6.4MPFS=6.6MAbstract ID：9027Abstract ID：9045612022/8/2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， TAK788K-RAS：AMG510，曲美替尼+多西他赛ALK：J-ALEX更新，Brigatinib 后线ROS1：RepotrectinibC-met：Tepotinib，CapmatinibRET：BLU-667Her-2：吡咯替尼B-raf: NTRKs：NCCN指南推荐检测八个基因+K-

29、RAS622022/8/2ROS1 inhibitors in TKI naive patientsPresented By Benjamin Besse at 2019 ASCO Annual Meeting（洛普替尼）（恩曲替尼）ROS1 inhibitors in TKI pretreated patientsPresented By Benjamin Besse at 2019 ASCO Annual MeetingROS1 inhibitorsPresented By Benjamin Besse at 2019 ASCO Annual Meeting主要内容EGFR： 克服耐药：J

30、NJ-372，U3-1402， 延缓耐药： RELAY研究，化疗+TKI，9291+A EGFR-20插入： JNJ-372， TAK788K-RAS：AMG510，曲美替尼+多西他赛ALK：J-ALEX更新，Brigatinib 后线ROS1：RepotrectinibC-met：Tepotinib，CapmatinibRET：BLU-667Her-2：吡咯替尼B-raf: NTRKs：NCCN指南推荐检测八个基因+K-RAS662022/8/2Paik Cancer Discovery 2015 * Tong - Clin Cancer Res 2016.Drilon A et al, J

31、 Thoracic Oncol, 2016.C-met异常肺癌672022/8/2C-met异常肺癌：第1类MET抑制剂Cui JJ, 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）682022/8/2C-met扩增肺癌：克唑替尼、Capmatinib692022/8/2C-met-14skipping肺癌：克唑替尼702022/8/2Capmatinib in METex14-mutated adva

32、nced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 studyPresented By Juergen Wolf at 2019 ASCO Annual MeetingGEOMETRY mono-1: A phase II trial of capmatinib in patients with advanced NSCLC harboring MET exon14 skipping mutationPresented By Juergen Wolf at 2019 A

33、SCO Annual Meeting Best overall response (pretreated cohort 4)Presented By Juergen Wolf at 2019 ASCO Annual MeetingBest overall response (treatment naive cohort 5b)Presented By Juergen Wolf at 2019 ASCO Annual MeetingTumor shrinkage per BIRCPresented By Juergen Wolf at 2019 ASCO Annual MeetingProgre

34、ssion-free survival per BIRCPresented By Juergen Wolf at 2019 ASCO Annual MeetingConclusions Presented By Juergen Wolf at 2019 ASCO Annual Meeting反应率：54%;7/13；4例CRPhase II study of tepotinib in NSCLC patients with METex14 mutations Presented By Paul Paik at 2019 ASCO Annual MeetingVISION study desig

35、nPresented By Paul Paik at 2019 ASCO Annual Meeting研究设计Efficacy: Best overall response (IRC/Investigator) Presented By Paul Paik at 2019 ASCO Annual Meeting客观有效率Efficacy: Tumor shrinkage by line of therapyPresented By Paul Paik at 2019 ASCO Annual Meeting疗效数据Efficacy: Progression-free survivalPresen

36、ted By Paul Paik at 2019 ASCO Annual MeetingPFS数据主要内容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， TAK788K-RAS：AMG510，曲美替尼+多西他赛ALK：J-ALEX更新，Brigatinib 后线ROS1：RepotrectinibC-met：Tepotinib，CapmatinibRET：BLU-667Her-2：吡咯替尼B-raf: NTRKs：NCCN指南推荐检测八个基因+K-RAS832022/8/2 NATURE R

37、EVIEWS | CLINICAL ONCOLOGY VOLUME 15 | MARCH 2018 | 151 RET阳性肺癌：凡德他尼、卡博替尼、LOXO-292842022/8/2BLU-667 Demonstrates Substantial Antitumor Activity in RET Fusion+ Advanced NSCLCPresented By Justin Gainor at 2019 ASCO Annual MeetingRET融合肺癌：BLU-667ORR=71%研究药物人数反应率无进展生存PFSDrilon A, 2016卡博替尼2528%未达到Lin JJ, 2016艾乐替尼450%治疗反应持续时间：6个月Lee SH, 2017凡德他尼1818%4.5 m.Yoh, K, 2017凡德他尼1953%4.7 m.Velcheti, 2016乐伐替尼2518%7.3 m.Gaustchi O, 2017不同注册中心药物不同5318 to 37%2.3 m.Subbiah V, 2018 (ASCO)凡德他尼 + 依维莫司1354% (7/13)4.4mJustin Gainor 2019 (ASC