EGFRTKI耐药后治疗策略

1、1会计学EGFRTKI耐药后治疗策略耐药后治疗策略 Major Mechanisms of Acquired Resistance Identified in Clinical Specimens Mechanism Estimated Frequency (%)EGFR TKI resistanceGenetic alterations in EGFRT790M mutations 50D761Y, T854A, and L747S mutations 5EGFR amplification 8Bypass signaling tractsMET amplification 5-22HER2

2、 amplification 12PIK3CA mutations 5BRAF mutations 1 HGF overexpression 1 of 2 casesPhenotypic alterationsTransformation to small-cell lung cancer 3-14ALK TKI resistanceGenetic alterations in ALK 所占比例% ALK secondary mutations (eg, L1196M) 22-36 ALK gene amplification 7-18 Bypass signaling tractsEGFR

3、activation 44KIT gene amplification 15Abbreviations: EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; HER2, human epidermal growth factor receptor 2; HGF, hepatocyte growth factor; ALK, anaplastic lymphoma kinase.疾病分期药物中位TTP参考文献CML原始细胞危象伊马替尼10月Sawyers et al, 2002 (缓解持续)GIST晚期伊

4、马替尼17月Heinrich et al, 2004 (无事件生存)肺癌晚期吉非替尼/厄洛替尼9-10月Mitsudomi et al, 2009Rosell et al, 2012肺癌晚期克唑替尼10月Camidge et al, 2011黑色素瘤晚期Vemurafenib7月Sosman et al, 2012Sequist et al. Sci Transl Med 2011, Adapted; Sequist, ASCO 2012.同时有EGFR扩增机制不明SCLC转化T790M肿瘤评价SD(大于6个月)肿瘤评价CR或PRJackman DM et al; J Clin Oncol.

5、2010; 28(2):357-60. Criteria for Acquired Resistance to EGFR Tyrosine Kinase Inhibitors1. Patient has received prior therapy with an EGFR TKI (monotherapy).2. Tumor genotyping confirms the presence of a typical EGFR mutationthat is associated with sensitivity to EGFR TKIs. Examples include exon19 de

6、letions, L858R, and G719X. ORPatient achieves either a documented partial or complete response ORprolonged stable disease ( 6 months) based on RECIST or WHO criteria.3. Disease progression occurs despite uninterrupted exposure to an EGFRTKI within 30 days.4. Patient has not received additional syste

7、mic therapy sincediscontinuation of EGFR TKIs. Adapted from Jackman et al.26 Abbreviations: EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.EGFR TKIPD获得性耐药721 天洗脱期临床试验14 disease flare47 completed washoutmPFS19个月Chaft, et al. Clin Cancer Res 201123% 发生疾病快速进展导致住院或死亡（flare）中位发生时间

8、：停药后8天相关因素: TTP短(P=0.002), 胸膜转移(P=0.03), CNS转移 (P=0.01), 与T790M无关仍有依赖TKI控制的肿瘤Yu HA, et al. 2012 ASCO Abstract 7527.局部治疗方法N=18肺15 射频消融(RFA)2 放疗2 肺叶切除7 楔形切除1 全肺切除3淋巴结放疗 (纵隔/锁骨上)1肾上腺切除200012243648204060801002040608010012243648600时间 (月)时间 (月)无进展生存率 总生存率 PFS (%)OS (%)Weickhardt AJ,et al. JTO.2012 Dec;7(1

9、2):1807-14 .Weickhardt AJ,et al. JTO.2012 Dec;7(12):1807-14 .首先进展部位NPFS1(95% CI)PFS2(95% CI)CNS和/或eCNS259.8个月8.8 13.86.2个月3.7 8.0PFS1: 9.8mPFS1 + PFS2: 9.8m+6.2m0255075100061218243036时间 (月)PFS (%)Weickhardt AJ,et al. JTO.2012 Dec;7(12):1807-14 .入组患者N=78化疗+厄洛替尼N=34化疗N=44Goldberg SB et al. 2012 ASCO A

10、bstract 7524.化疗+厄洛替尼(N=34)化疗(n=44)OR/HR95%CI; P值ORR (%)4118OR 0.20 (0.05-0.78)0.02中位PFS (月)4.44.2HR 0.79 (0.48-1.29)0.34Goldberg SB et al. 2012 ASCO Abstract 7524.Goldberg SB et al. 2012 ASCO Abstract 7524.化疗 + 厄洛替尼相比基线的自家改善百分比 (%)4020020406080PD或SDPR化疗4020020406080PD或SDPRPRPD/SDPRPD/SDAsami K, et a

11、l. Lung Cancer 2013; 79:276-282.易瑞沙组短期3M (n=66)长期3M (n=68)P值PD前：CR/PR44 (67%)31 (46%)0.01出现PD时 PFS 9个月49 (74%)58 (85%)0.11 ECOG PS 0-125 (38%)49 (72%)0.001 既往评估病灶进展23 (35%)42 (62%)0.002PD后：后续治疗44 (67%)31 (46%)0.01Asami K, et al. Lung Cancer 2013; 79:276-282.易瑞沙组P值HR95%CIECOG PS0.0480.60.36-0.99PFS 9

12、个月0.270.80.5-1.2既往评估病灶进展0.020.60.39-0.92易瑞沙长期治疗组5年 (n=28)性别：男/女 (%)29.3/70.710.7/89.3吸烟状态：否/是/未知 (%)64.8/32.2/3.078.6/17.9/3.6分期：IIIA/IIIB/IV (%)1.5/19.7/80.30/28.6/71.4WHO PS：0/1/2/未知 (%)18.3/69.1/12.6/0.632.1/64.3/3.6/0.0组织学：腺癌/鳞癌/大细胞癌/其他 (%)90.3/7.3/0.9/2.796.3/0/3.6/3.6中位治疗时间 (天)267.0926吉非替尼再次挑战

13、 (%)19.450.0进展后继续吉非替尼治疗 (%)27.839.3Namba Y, et al. 2012 ESMO, abstract 1253P. 1008060402000200400600800100012001400时间 (天)吉非替尼再挑战 (n=65)：中位1272天未接受吉非替尼再挑战 (n=270)：中位774天P0.001OS (%)Namba Y, et al. 2012 ESMO, abstract 1253P. 单变量分析多变量分析点估计值95%CIP值点估计值95%CIP值下限上限下限上限性别女/男0.7280.5470.9700.03040.8740.6241

14、.2240.4338分期IV/IIIB1.4371.0122.0420.04301.3550.9471.9400.0961年龄5160/500.8150.4911.3540.13680.7480.4451.2580.02696170/500.9450.5831.5310.9360.5701.5397180/501.2800.7752.1151.2270.7302.06481/501.4800.6733.2542.0870.9364.652组织学腺癌/非腺癌1.0350.3303.2460.95300.9600.3003.0750.9452PS连续值1.1220.9841.2810.08631.

15、1620.9991.3530.0519吸烟状态连续值1.1161.0321.2080.00611.1041.0081.2100.0335再次给予 吉非替尼是/否0.5190.3710.7260.00010.5170.3640.7340.0002120 trial patients 107 routine patients227例III/IV期NSCLC患者Yang JJ, et al. Lung Cancer. 2013 Jan;79(1):33-9.57.3%(130/227)24.2%(55/227)18.5%(42/227)爆发进展:缓慢进展局部进展Yang JJ, et al. Lun

16、g Cancer. 2013 Jan;79(1):33-9. 疾病控制3个月 与以往评估相比，肿瘤负荷快速增加 症状评分达到2 疾病控制6个月 与以往评估相比，肿瘤负荷轻微增加 症状评分达到1 疾病控制3个月 孤立性颅外进展或颅内进展 症状评分达到1N中位(月)P爆发 1309.3缓慢4212.90.007局部559.2N中位P爆发 13017.1缓慢 4239.43个月RECIST评价：厄洛替尼治疗后PR或CR的患者或EGFR外显子19或21突变EGFR突变与MET扩增的患者PD后病灶活检停止厄洛替尼治疗2周接受阿法替尼40mg/d PO，治疗2周阿法替尼40mg PO每日并联合西妥昔单抗每

17、2周静脉用药(I期临床研究的剂量)Janjigian YY, et al. ASCO 2011; Abstract 7525.Janjigian YY, et al. ASCO 2011; Abstract 7525.706050403020100-10-20-30-40-50-60-70-80-90-10001648122024283236404448自基线减小的最大比例 (%)T790M+T790M-无突变无价值Zhou WJ, et al. Nature 2009; 462:1070-1074.NNNHYNNXCINH02040608010002040608010002040608010

18、02001801601401201001008060402004,0003,0002,0001,0001008060402004,0003,0002,0001,0001008060402004,0003,0002,0001,0001008060402004,0003,0002,0001,000100806040200H3255PC9H1975PC9 GRE746_A750/T790ML858R/T790ME746_A750L858RIC50 (Nm)IC50 (Nm)CL-387,785HKI-272WZ3146WZ4002WZ8040WZ3146 X=O, Y=HWZ4002 X=O, Y=

19、OMeWZ8040 X=S, Y=H易瑞沙机制策略临床研究 (例)T790MEGFR抑制剂的联合T-790M特异性TKIMET+PI3K抑制剂Hsp90抑制剂阿法替尼+西妥昔单抗CO-1686, AP26113GDC-0973+GDC-0941AUY922C-MET扩增EGFR+c-MET抑制剂厄洛替尼+克唑替尼Dacomitinib+克唑替尼SCLC转化铂类/依托泊苷+/-EGFR TKI无PIK3CAEGFR+PI3K抑制剂吉非替尼+BKM120厄洛替尼+GDC-0941未知EGFR抑制剂联合Hsp90抑制剂阿法替尼+西妥昔单抗厄洛替尼+AUY922EGFR mut+NSCLCResist

20、anceEGFR TKI- T790M - MET amp- HGF overexp- MiscNew agentsChemotherapyEGFR TKI continuation + chemotherapyLocal therapy RT, SurgeryT790MMETOther- Irreversible EGFR-TKI- Mutant specific TKI- MET-TKI + EGFR-TKI- MET MAb + EGFR-TKI- Anti-HGF AB+ EGFR-TKI- Irrev EGFR TKI + cetuximab- HSP90 inhibitorT790

21、M mutationMet ampPIK3CASCLCHER2-ampMAPK1 ampAXL expressionSequist et al Sci Trans Med 2011Cheung HW et al Cancer Discovery 2011Etcan et al Cancer Discovery 2012Takezawa et al Cancer Discovery 2012Zhang et al Nature Genetics 2012 ALK TKI resistanceGenetic alterations in ALK 所占比例% ALK secondary mutati

22、ons (eg, L1196M) 22-36 ALK gene amplification 7-18 Bypass signaling tractsEGFR activation 44KIT gene amplification 15Abbreviations: EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; HER2, human epidermal growth factor receptor 2; HGF, hepatocyte growth factor; ALK, anaplastic lymphoma kinase.疾病分期药物中位TTP参考文献CML原始细胞危象伊马替尼10月Sawyers et al, 2002 (缓解持续)GIST晚期伊马替尼