EGFRTKI治療NSCLC腦轉(zhuǎn)移研究進(jìn)展

1、1會(huì)計(jì)學(xué)EGFRTKI治療治療NSCLC腦轉(zhuǎn)移研究進(jìn)展腦轉(zhuǎn)移研究進(jìn)展23Sperduto PW, et al. J Clin Oncol. 2012 Feb 1;30E.J.Dropcho,Neurologic complications of lung cancer.2014中位OS (月)不治療0.25mm時(shí)血腦屏障通透性增加 腦轉(zhuǎn)移發(fā)生后，TKIs在CSF中的濃度增加？ Fidler IJ,et al.Lancet Oncol,2002,3:53-7.發(fā)生腦轉(zhuǎn)移可能導(dǎo)致血腦屏障的破壞腦轉(zhuǎn)移的發(fā)生可改變血腦屏障結(jié)構(gòu)CSF通透率 %P=0.042吉非替尼在有腦轉(zhuǎn)移的NSCLC中CSF通透率更

2、高 檢測(cè)吉非替尼在22例中國(guó)NSCLC患者腦脊液中的濃度l通常認(rèn)為吉非替尼不能大量的通過(guò)血腦屏障. 在中國(guó)的臨床實(shí)驗(yàn)中, 接受每天250mg給藥的伴腦轉(zhuǎn)移的患者中吉非替尼在CSF中的通透率約為2%l該研究顯示，伴有腦轉(zhuǎn)移的患者吉非替尼在CSF中的濃度表現(xiàn)出高于不伴有腦轉(zhuǎn)移的患者的特征。其中一種假說(shuō)就是腦轉(zhuǎn)移會(huì)破壞血腦屏障. 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腦組織中濃度結(jié)論：

3、lCSF 藥物濃度/血藥濃度與既往報(bào)道人類(lèi)研究數(shù)據(jù)相似；l 腦組織藥物濃度遠(yuǎn)高于CSF藥物濃度（數(shù)十倍甚至上百倍的差距），與人體藥代動(dòng)力學(xué)腫瘤組織藥物濃度/血藥濃度相似，再次驗(yàn)證吉非替尼富集于腫瘤組織的特性。l 提高吉非替尼的劑量可使腦轉(zhuǎn)移灶的藥物濃度升高。吉非替尼在NSCLC腦轉(zhuǎn)移瘤組織的濃度 Mengzhao Wang, et al. Lung Cancer.2013 Nov;82(2):313-8.造影劑釓注射后頭顱MRI的T1加權(quán)圖像：小腦有兩個(gè)增強(qiáng)信號(hào)的轉(zhuǎn)移病灶把C11-厄洛替尼作為示蹤劑的PET/CT圖像和頭顱MRI圖像進(jìn)行整合：小腦的這兩個(gè)轉(zhuǎn)移病灶有明顯的C11-厄洛替尼濃聚正常

4、腦組織則沒(méi)有C11-厄洛替尼濃聚J Thorac Oncol. 2011;6: 12871289.EGFR-TKI可在NSCLC顱內(nèi)轉(zhuǎn)移灶聚集透過(guò)血腦屏障的比例透過(guò)血腦屏障的比例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在腦脊液中的濃度厄洛替尼透過(guò)血腦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血漿蛋白結(jié)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.推薦劑量下： 厄洛替尼的血藥濃度遠(yuǎn)高于吉非替尼厄洛替尼的血漿蛋白結(jié)合率低于吉非替尼

7、厄洛替尼透過(guò)血腦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濃度和腦轉(zhuǎn)移灶緩解率對(duì)比Togashi et al. Cancer Chemother Pharmacol (2012) 70:399405.在該實(shí)驗(yàn)中，盡管厄洛替尼組的CSF濃度高于吉非替尼，但兩組在腦轉(zhuǎn)移患者中的療效沒(méi)有顯著差異 (G1/3 vs. E4/7, Fisher檢驗(yàn), P = 1.00)24EGFR-TKI (n=101)化療化療 (n=54)P值值中位年齡 (范圍) (歲)63 (35-84)60 (32-85)0.38男/女 (%)23/7739/610.04白-非西裔/亞裔/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/鱗/大細(xì)胞/NSCLC NOS (%)9/0/0/987/4/2/70.11既往腦轉(zhuǎn)移 (%)24221.00既往腦轉(zhuǎn)移治療：放療/切除+放療/無(wú) (n)21/1/26/4/2-Heon S, et al. Clin Cancer Res 2012; 18(16):4406-4414. 日本多中心回顧性研究 IV期或全身復(fù)發(fā)的I-IIIA期NSCLC EGFR敏感突變 隨訪(fǎng)至少1年 N=155EGFR-TKI(吉非替尼89%或厄洛替尼11%) (n=

9、101)化療 (n=54)含鉑兩藥91%；單藥7%；其他聯(lián)合方案2%CNS進(jìn)展累積風(fēng)險(xiǎn)6個(gè)月個(gè)月12個(gè)月個(gè)月24個(gè)月個(gè)月EGFR-TKI (n=101)1%6%21%化療 (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個(gè)月個(gè)月12個(gè)月個(gè)月24個(gè)月個(gè)月EGFR-TKI (n=77)1%3%15%化療 (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.吉非替尼單藥治療EGFR突變的肺腺癌伴腦轉(zhuǎn)移的療效的研究設(shè)計(jì)日本進(jìn)行的一項(xiàng)前瞻性II期臨床研究試驗(yàn)入組標(biāo)準(zhǔn)：l病理學(xué)確認(rèn)的NSCLClEGFR基因突變（原發(fā)灶/直接測(cè)序法）l影像學(xué)確認(rèn)的腦轉(zhuǎn)移患者l既往未接受化療或TKI治療l18歲lECOG PS： 2分l排除因外科切除導(dǎo)致神經(jīng)癥狀的腦轉(zhuǎn)移吉非替尼250mg/天主要終點(diǎn)：客觀緩解率ORR次要終點(diǎn)：無(wú)進(jìn)展生存PFS至放射治療時(shí)間安全性T. luchi, et al.Lung Cancer,82(201

11、3)282-287緩解率結(jié)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%)吉非替尼對(duì)不同EGFR突變類(lèi)型腦轉(zhuǎn)移的療效T. luchi, et al.Lung Cancer,82(2013)282-287l根據(jù)不同的患者特征進(jìn)行的

12、亞組分析中，無(wú)論從性別、年齡、吸煙狀態(tài)、體力評(píng)分、顱內(nèi)病灶數(shù)、腫瘤大小和DS-GPA分組中，客觀緩解都未見(jiàn)統(tǒng)計(jì)學(xué)差距。研究結(jié)果顱內(nèi)中位至疾病進(jìn)展時(shí)間在吉非替尼治療期間，共有15位患者CNS出現(xiàn)進(jìn)展全組人群不同基因型mCNS PFS: 14.5個(gè)月(95%CI 10.218.3) 19Del17.5 月月L858R10.2 月T. luchi, et al.Lung Cancer,82(2013)282-287研究結(jié)果中位至挽救性放療時(shí)間全組人群不同基因型mTTSI*: 17.9個(gè)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研究結(jié)果中位總生存期全組人群不同基因型mOS: 21.9個(gè)月(95% CI 18.530.3)19Del30.3 月月L858R19.8 月T. luchi, et al.Lung Cancer,82(2013)282-287l該研究驗(yàn)證了吉非替尼單藥對(duì)于EGFR突變伴腦轉(zhuǎn)移患者的療效令人滿(mǎn)意，ORR：87.8%，并能有一半的患者可以延遲1.5年的至放療時(shí)間l19Del較L858R突變的伴腦轉(zhuǎn)移的NSCLC患者有更好的預(yù)后研究結(jié)論T. luchi, et al.Lung

14、Cancer,82(2013)282-287一代TKI對(duì)腦轉(zhuǎn)移療效匯總分析l EGFR TKI治療腦轉(zhuǎn)移的NSCLC患者，顱內(nèi)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對(duì)腦轉(zhuǎn)移療效lEGFR M+腦轉(zhuǎn)移患者，EGFR-TKI療效肯定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放射學(xué)診斷的NSCLC腦轉(zhuǎn)移有/無(wú)SRS

26、或開(kāi)顱手術(shù)史18歲KPS 70 （40例）研究終點(diǎn)：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維持 WBRT (2.5 Gy/d5 d/w , 共計(jì)35 Gy）l中心實(shí)驗(yàn)室EGFR 突變狀態(tài)檢測(cè)18-21外顯子l中位隨訪(fǎng)時(shí)間28.5個(gè)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狀態(tài)已知病人的總生存l 無(wú)CNS進(jìn)展的病人的生存情況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、位易瑞沙治療至開(kāi)始WBRT的間隔時(shí)間為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中位年齡 (范圍) (歲)56 (24-81)52 (30-74)0.29PS 0-2/3-4 (%)71.1/28.975.6/24.40.634不或輕度吸煙/中度吸煙 (%)75.6/24.473.3/26.70.81腦轉(zhuǎn)移數(shù)：5/5 (%)44.4/55.655.6/44.40.29腦轉(zhuǎn)移大?。?20mm/20mm (%)93.3/6.777.8/22.2-EGFR突變：陰性/陽(yáng)性/未知 (%)11.1/11.1/77

29、.86.7/15.6/77.80.71顱外轉(zhuǎn)移器官數(shù)：0/1/2 (%)24.4/35.6/4017.8/51.1/31.10.33既往化療數(shù)：0/1/2 (%)42.2/35.6/22.260.0/26.7/13.30.23既往胸部放療：是/否 (%)13.3/86.713.3/86.71.00 組織學(xué)診斷為肺腺癌 確認(rèn)腦轉(zhuǎn)移 至少1個(gè)可測(cè)量腦轉(zhuǎn)移且直徑10mm 既往未接受手術(shù)、手術(shù)放療、EGFR-TKI或WBRT 完整醫(yī)療記錄 (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/癥狀?lèi)夯?不可接受的毒性WBRT40Gy/20fr*n=45n=45直至PD/癥

30、狀?lèi)夯?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個(gè)月l吉非替尼(n=45)：中位6.57個(gè)月l吉非替尼-WBRT (n=45)：中位23.4個(gè)月l吉非替尼 (n=45)：

31、中位14.83個(gè)月5253545556NCCN指南關(guān)于NSCLC腦轉(zhuǎn)移的治療IV期期M1b轉(zhuǎn)移灶數(shù)轉(zhuǎn)移灶數(shù)目局限目局限腦轉(zhuǎn)移灶：腦轉(zhuǎn)移灶：手術(shù)切除手術(shù)切除+WBRT或或SRS或或SRS+WBRT或僅或僅SRS原發(fā)灶：手術(shù)切除/SABR后化療或化療后手術(shù)/SABRIV期不可手術(shù)EGFR突變陽(yáng)性孤立病灶：TKI+局部治療多發(fā)病灶：WBRT+TKINCCN關(guān)于NSCLC腦轉(zhuǎn)移的治療NCCN關(guān)于NSCLC腦轉(zhuǎn)移的治療60感謝關(guān)注！Bhatt VR et al.2015 WCLC mini10.14Bhatt VR et al.2015 WCLC mini10.14非小細(xì)胞肺癌腦轉(zhuǎn)移情況及EGFR突變狀態(tài)的研究結(jié)論Villano JL,et al. Ann Oncol,2003,14:656-8.首例Gefibinib治療NSCLC腦轉(zhuǎn)移吉非替尼和厄洛替尼的CSF濃度和腦轉(zhuǎn)移灶緩解率對(duì)比Togashi et al. Cancer Chemother Pharmacol (2012) 70