EGFRTKI治疗NSCLC脑转移研究进展

1、1会计学EGFRTKI治疗治疗NSCLC脑转移研究进展脑转移研究进展23Sperduto PW, et al. J Clin Oncol. 2012 Feb 1;30E.J.Dropcho,Neurologic complications of lung cancer.2014中位OS (月)不治疗0.25mm时血脑屏障通透性增加 脑转移发生后，TKIs在CSF中的浓度增加？ Fidler IJ,et al.Lancet Oncol,2002,3:53-7.发生脑转移可能导致血脑屏障的破坏脑转移的发生可改变血脑屏障结构CSF通透率 %P=0.042吉非替尼在有脑转移的NSCLC中CSF通透率更

2、高 检测吉非替尼在22例中国NSCLC患者脑脊液中的浓度l通常认为吉非替尼不能大量的通过血脑屏障. 在中国的临床实验中, 接受每天250mg给药的伴脑转移的患者中吉非替尼在CSF中的通透率约为2%l该研究显示，伴有脑转移的患者吉非替尼在CSF中的浓度表现出高于不伴有脑转移的患者的特征。其中一种假说就是脑转移会破坏血脑屏障. Jin Zhao, et al Clin Lung Cancer. 2013 Mar;14(2):188-93.Mckillop D,et al.Xenobiotica,2004,34(10):917-34.Cbrain/Clung：2%吉非替尼在健康小鼠脑组织中浓度结论：

3、lCSF 药物浓度/血药浓度与既往报道人类研究数据相似；l 脑组织药物浓度远高于CSF药物浓度（数十倍甚至上百倍的差距），与人体药代动力学肿瘤组织药物浓度/血药浓度相似，再次验证吉非替尼富集于肿瘤组织的特性。l 提高吉非替尼的剂量可使脑转移灶的药物浓度升高。吉非替尼在NSCLC脑转移瘤组织的浓度 Mengzhao Wang, et al. Lung Cancer.2013 Nov;82(2):313-8.造影剂钆注射后头颅MRI的T1加权图像：小脑有两个增强信号的转移病灶把C11-厄洛替尼作为示踪剂的PET/CT图像和头颅MRI图像进行整合：小脑的这两个转移病灶有明显的C11-厄洛替尼浓聚正常

4、脑组织则没有C11-厄洛替尼浓聚J Thorac Oncol. 2011;6: 12871289.EGFR-TKI可在NSCLC颅内转移灶聚集透过血脑屏障的比例透过血脑屏障的比例1.Yosuke Togashi et al, Cancer Chemother Pharmacol, 2011, 68:1089-1092;2.Aleberto B et al. Clin Cancer Res 2007;13:1511-1515;3. Masuda T,et al.Cancer Chemo Pharm,2011,67:1465-1469;4. Togashi Y,et al.J Thorac Onc

5、ol,2010,5:950-955; 5.Tohoku J. Exp. Med 2008,214,359-363;3.J Clin Oncol. 2006 Sep 20;24(27):4517-20;6.Wang M et al. J Clin Oncol, 29,2011,abstract 76081TKI在脑脊液中的浓度厄洛替尼透过血脑屏障的比例高于吉非替尼65432厄洛替尼厄洛替尼3吉非替尼吉非替尼4血浆蛋白结合率93%97%厄洛替尼厄洛替尼1( 150mg/d )吉非替尼吉非替尼2( 225mg/d )吉非替尼吉非替尼2( 525mg/d )吉非替尼吉非替尼2( 700mg/d )Cm

6、ax(ng/ml)2,1203079032,146AUC0-24(nghour/mL)38,4205,04114,72736,0771.Hidalgo M, et al. J Clin Oncol 2001;19:32673279. 2. Ranson M, et al. J Clin Oncol 2002;20:224022503. Johnson JR, et al. Clin Cancer Res 11:64146421. 4. Li J,et al. Invest New Drugs 24:291297.推荐剂量下： 厄洛替尼的血药浓度远高于吉非替尼厄洛替尼的血浆蛋白结合率低于吉非替尼

7、厄洛替尼透过血脑屏障的比例高于吉非替尼的可能原因吉非替尼和厄洛替尼的CSF浓度和脑转移灶缓解率对比Togashi et al. Cancer Chemother Pharmacol (2012) 70:399405.在该实验中，尽管厄洛替尼组的CSF浓度高于吉非替尼，但两组在脑转移患者中的疗效没有显著差异 (G1/3 vs. E4/7, Fisher检验, P = 1.00)24EGFR-TKI (n=101)化疗化疗 (n=54)P值值中位年龄 (范围) (岁)63 (35-84)60 (32-85)0.38男/女 (%)23/7739/610.04白-非西裔/亚裔/黑/西 (%)85/12

8、/3/092/0/4/410包年 (%)57/19/2437/30/330.05ECOG PS 0-1/2+ (%)94/685/110.34腺/鳞/大细胞/NSCLC NOS (%)9/0/0/987/4/2/70.11既往脑转移 (%)24221.00既往脑转移治疗：放疗/切除+放疗/无 (n)21/1/26/4/2-Heon S, et al. Clin Cancer Res 2012; 18(16):4406-4414. 日本多中心回顾性研究 IV期或全身复发的I-IIIA期NSCLC EGFR敏感突变 随访至少1年 N=155EGFR-TKI(吉非替尼89%或厄洛替尼11%) (n=

9、101)化疗 (n=54)含铂两药91%；单药7%；其他联合方案2%CNS进展累积风险6个月个月12个月个月24个月个月EGFR-TKI (n=101)1%6%21%化疗 (n=54)7%19%32%Heon S, et al. Clin Cancer Res 2012; 18(16):4406-4414.Heon S, et al. Clin Cancer Res. 2012. 18(16): 44064414.6个月个月12个月个月24个月个月EGFR-TKI (n=77)1%3%15%化疗 (n=42)7%17%30%Heon S, et al. Clin Cancer Res 2012

10、; 18(16):4406-4414.Heon S, et al. Clin Cancer Res 2012; 18(16):4406-4414.吉非替尼单药治疗EGFR突变的肺腺癌伴脑转移的疗效的研究设计日本进行的一项前瞻性II期临床研究试验入组标准：l病理学确认的NSCLClEGFR基因突变（原发灶/直接测序法）l影像学确认的脑转移患者l既往未接受化疗或TKI治疗l18岁lECOG PS： 2分l排除因外科切除导致神经症状的脑转移吉非替尼250mg/天主要终点：客观缓解率ORR次要终点：无进展生存PFS至放射治疗时间安全性T. luchi, et al.Lung Cancer,82(201

11、3)282-287缓解率结果All patientsEx19 deletionEx21 L858RPatients number412315CR13 (31.7%)10 (43.5%)3 (20.0%)PR23 (56.1%)13 (56.5%)9 (60.0%)CR + PR36 (87.8%)23 (100.0%)12 (80.0%)SD4 (9.8%)0 (0.0%)3 (20.0%)PD1 (2.4%)0 (0.0%)0 (0.0%)吉非替尼对不同EGFR突变类型脑转移的疗效T. luchi, et al.Lung Cancer,82(2013)282-287l根据不同的患者特征进行的

12、亚组分析中，无论从性别、年龄、吸烟状态、体力评分、颅内病灶数、肿瘤大小和DS-GPA分组中，客观缓解都未见统计学差距。研究结果颅内中位至疾病进展时间在吉非替尼治疗期间，共有15位患者CNS出现进展全组人群不同基因型mCNS PFS: 14.5个月(95%CI 10.218.3) 19Del17.5 月月L858R10.2 月T. luchi, et al.Lung Cancer,82(2013)282-287研究结果中位至挽救性放疗时间全组人群不同基因型mTTSI*: 17.9个月(95% CI 12.424.7)*median time to salvage irradiation 19De

13、l18.4 月月L858R13.1 月T. luchi, et al.Lung Cancer,82(2013)282-287研究结果中位总生存期全组人群不同基因型mOS: 21.9个月(95% CI 18.530.3)19Del30.3 月月L858R19.8 月T. luchi, et al.Lung Cancer,82(2013)282-287l该研究验证了吉非替尼单药对于EGFR突变伴脑转移患者的疗效令人满意，ORR：87.8%，并能有一半的患者可以延迟1.5年的至放疗时间l19Del较L858R突变的伴脑转移的NSCLC患者有更好的预后研究结论T. luchi, et al.Lung

14、Cancer,82(2013)282-287一代TKI对脑转移疗效汇总分析l EGFR TKI治疗脑转移的NSCLC患者，颅内ORR51.8%，DCR 75.7%, mPFS 7.4m，mOS 11.9mFan,Y et al. Onco Targets Ther.2014 Nov 10Fan,Y et al. Onco Targets Ther.2014 Nov 10一代TKI对脑转移疗效lEGFR M+脑转移患者，EGFR-TKI疗效肯定Confidentiality Notice This file is private and may contain confidential and

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25、t you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful. AstraZeneca PLC, 2 Kingdom Street, London, W2 6BD, UK, T: +44(0)20 7604 8000, F: +44 (0)20 7604 8151, 444546放射学诊断的NSCLC脑转移有/无SRS

26、或开颅手术史18岁KPS 70 （40例）研究终点：OSORRTTP安全性厄洛替尼厄洛替尼150 mg /d +WBRT厄洛替尼厄洛替尼150 mg/d维持 WBRT (2.5 Gy/d5 d/w , 共计35 Gy）l中心实验室EGFR 突变状态检测18-21外显子l中位随访时间28.5个月（19.6-37.9m）Welsh et al.JCO March 1, 2013 vol. 31 no. 7 895-902 47l Overall survival for all patientsl Survival without CNS progression for all patients1

27、1.8m8.0mWelsh et al.JCO March 1, 2013 vol. 31 no. 7 895-902 2021-12-1448l EGFR状态已知病人的总生存l 无CNS进展的病人的生存情况All Patients(n= 17)EGFR- (n= 8)EGFR+ (n= 9)OS 12.8m9.3m19.1mCNS PFS8.2m5.2m12.3mWelsh et al.JCO March 1, 2013 vol. 31 no. 7 895-902 Zeng YD, et al. Asian Pacifici J Cancer Prev 2012; 13:909-914.*中

28、位易瑞沙治疗至开始WBRT的间隔时间为15天(0-34天)吉非替尼(n=45)吉非替尼+WBRT (n=45)P值男/女 (%)42.4/57.846.7/53.30.67中位年龄 (范围) (岁)56 (24-81)52 (30-74)0.29PS 0-2/3-4 (%)71.1/28.975.6/24.40.634不或轻度吸烟/中度吸烟 (%)75.6/24.473.3/26.70.81脑转移数：5/5 (%)44.4/55.655.6/44.40.29脑转移大小： 20mm/20mm (%)93.3/6.777.8/22.2-EGFR突变：阴性/阳性/未知 (%)11.1/11.1/77

29、.86.7/15.6/77.80.71颅外转移器官数：0/1/2 (%)24.4/35.6/4017.8/51.1/31.10.33既往化疗数：0/1/2 (%)42.2/35.6/22.260.0/26.7/13.30.23既往胸部放疗：是/否 (%)13.3/86.713.3/86.71.00 组织学诊断为肺腺癌 确认脑转移 至少1个可测量脑转移且直径10mm 既往未接受手术、手术放疗、EGFR-TKI或WBRT 完整医疗记录 (N=90)吉非替尼吉非替尼250mg/d吉非替尼吉非替尼 250mg/d直至PD/症状恶化/不可接受的毒性WBRT40Gy/20fr*n=45n=45直至PD/症

30、状恶化/不可接受的毒性Zeng YD, et al. Asian Pacifici J Cancer Prev 2012; 13:909-914.26.742.264.471.1020406080100ORRDCR吉非替尼 (n=45)吉非替尼+WBRT (n=45)P0.001P=0.006患者 (%)Zeng YD, et al. Asian Pacifici J Cancer Prev 2012; 13:909-914.l吉非替尼-WBRT (n=45)：中位10.6个月l吉非替尼(n=45)：中位6.57个月l吉非替尼-WBRT (n=45)：中位23.4个月l吉非替尼 (n=45)：

31、中位14.83个月5253545556NCCN指南关于NSCLC脑转移的治疗IV期期M1b转移灶数转移灶数目局限目局限脑转移灶：脑转移灶：手术切除手术切除+WBRT或或SRS或或SRS+WBRT或仅或仅SRS原发灶：手术切除/SABR后化疗或化疗后手术/SABRIV期不可手术EGFR突变阳性孤立病灶：TKI+局部治疗多发病灶：WBRT+TKINCCN关于NSCLC脑转移的治疗NCCN关于NSCLC脑转移的治疗60感谢关注！Bhatt VR et al.2015 WCLC mini10.14Bhatt VR et al.2015 WCLC mini10.14非小细胞肺癌脑转移情况及EGFR突变状态的研究结论Villano JL,et al. Ann Oncol,2003,14:656-8.首例Gefibinib治疗NSCLC脑转移吉非替尼和厄洛替尼的CSF浓度和脑转移灶缓解率对比Togashi et al. Cancer Chemother Pharmacol (2012) 70