1、1會計學EGFRTKI治療治療NSCLC腦轉移研究進展腦轉移研究進展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時血腦屏障通透性增加 腦轉移發生后，TKIs在CSF中的濃度增加？ Fidler IJ,et al.Lancet Oncol,2002,3:53-7.發生腦轉移可能導致血腦屏障的破壞腦轉移的發生可改變血腦屏障結構CSF通透率 %P=0.042吉非替尼在有腦轉移的NSCLC中CSF通透率更

2、高 檢測吉非替尼在22例中國NSCLC患者腦脊液中的濃度l通常認為吉非替尼不能大量的通過血腦屏障. 在中國的臨床實驗中, 接受每天250mg給藥的伴腦轉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，伴有腦轉移的患者吉非替尼在CSF中的濃度表現出高于不伴有腦轉移的患者的特征。其中一種假說就是腦轉移會破壞血腦屏障. 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論：

3、lCSF 藥物濃度/血藥濃度與既往報道人類研究數據相似；l 腦組織藥物濃度遠高于CSF藥物濃度（數十倍甚至上百倍的差距），與人體藥代動力學腫瘤組織藥物濃度/血藥濃度相似，再次驗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移灶的藥物濃度升高。吉非替尼在NSCLC腦轉移瘤組織的濃度 Mengzhao Wang, et al. Lung Cancer.2013 Nov;82(2):313-8.造影劑釓注射后頭顱MRI的T1加權圖像：小腦有兩個增強信號的轉移病灶把C11-厄洛替尼作為示蹤劑的PET/CT圖像和頭顱MRI圖像進行整合：小腦的這兩個轉移病灶有明顯的C11-厄洛替尼濃聚正常

4、腦組織則沒有C11-厄洛替尼濃聚J Thorac Oncol. 2011;6: 12871289.EGFR-TKI可在NSCLC顱內轉移灶聚集透過血腦屏障的比例透過血腦屏障的比例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高于吉非替尼厄洛替尼的血漿蛋白結合率低于吉非替尼

7、厄洛替尼透過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濃度和腦轉移灶緩解率對比Togashi et al. Cancer Chemother Pharmacol (2012) 70:399405.在該實驗中，盡管厄洛替尼組的CSF濃度高于吉非替尼，但兩組在腦轉移患者中的療效沒有顯著差異 (G1/3 vs. E4/7, Fisher檢驗, 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/大細胞/NSCLC NOS (%)9/0/0/987/4/2/70.11既往腦轉移 (%)24221.00既往腦轉移治療：放療/切除+放療/無 (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期或全身復發的I-IIIA期NSCLC EGFR敏感突變 隨訪至少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%；其他聯合方案2%CNS進展累積風險6個月個月12個月個月24個月個月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個月個月12個月個月24個月個月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移的療效的研究設計日本進行的一項前瞻性II期臨床研究試驗入組標準：l病理學確認的NSCLClEGFR基因突變（原發灶/直接測序法）l影像學確認的腦轉移患者l既往未接受化療或TKI治療l18歲lECOG PS： 2分l排除因外科切除導致神經癥狀的腦轉移吉非替尼250mg/天主要終點：客觀緩解率ORR次要終點：無進展生存PFS至放射治療時間安全性T. luchi, et al.Lung Cancer,82(201

11、3)282-287緩解率結果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%)吉非替尼對不同EGFR突變類型腦轉移的療效T. luchi, et al.Lung Cancer,82(2013)282-287l根據不同的患者特征進行的

12、亞組分析中，無論從性別、年齡、吸煙狀態、體力評分、顱內病灶數、腫瘤大小和DS-GPA分組中，客觀緩解都未見統計學差距。研究結果顱內中位至疾病進展時間在吉非替尼治療期間，共有15位患者CNS出現進展全組人群不同基因型mCNS PFS: 14.5個月(95%CI 10.218.3) 19Del17.5 月月L858R10.2 月T. luchi, et al.Lung Cancer,82(2013)282-287研究結果中位至挽救性放療時間全組人群不同基因型mTTSI*: 17.9個月(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研究結果中位總生存期全組人群不同基因型mOS: 21.9個月(95% CI 18.530.3)19Del30.3 月月L858R19.8 月T. luchi, et al.Lung Cancer,82(2013)282-287l該研究驗證了吉非替尼單藥對于EGFR突變伴腦轉移患者的療效令人滿意，ORR：87.8%，并能有一半的患者可以延遲1.5年的至放療時間l19Del較L858R突變的伴腦轉移的NSCLC患者有更好的預后研究結論T. luchi, et al.Lung

14、Cancer,82(2013)282-287一代TKI對腦轉移療效匯總分析l EGFR TKI治療腦轉移的NSCLC患者，顱內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對腦轉移療效lEGFR M+腦轉移患者，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放射學診斷的NSCLC腦轉移有/無SRS

26、或開顱手術史18歲KPS 70 （40例）研究終點：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35 Gy）l中心實驗室EGFR 突變狀態檢測18-21外顯子l中位隨訪時間28.5個月（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狀態已知病人的總生存l 無CNS進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、位易瑞沙治療至開始WBRT的間隔時間為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腦轉移數：5/5 (%)44.4/55.655.6/44.40.29腦轉移大小： 20mm/20mm (%)93.3/6.777.8/22.2-EGFR突變：陰性/陽性/未知 (%)11.1/11.1/77

29、.86.7/15.6/77.80.71顱外轉移器官數：0/1/2 (%)24.4/35.6/4017.8/51.1/31.10.33既往化療數：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 組織學診斷為肺腺癌 確認腦轉移 至少1個可測量腦轉移且直徑10mm 既往未接受手術、手術放療、EGFR-TKI或WBRT 完整醫療記錄 (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/癥狀惡化/不可接受的毒性WBRT40Gy/20fr*n=45n=45直至PD/癥

30、狀惡化/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個月l吉非替尼(n=45)：中位6.57個月l吉非替尼-WBRT (n=45)：中位23.4個月l吉非替尼 (n=45)：

31、中位14.83個月5253545556NCCN指南關于NSCLC腦轉移的治療IV期期M1b轉移灶數轉移灶數目局限目局限腦轉移灶：腦轉移灶：手術切除手術切除+WBRT或或SRS或或SRS+WBRT或僅或僅SRS原發灶：手術切除/SABR后化療或化療后手術/SABRIV期不可手術EGFR突變陽性孤立病灶：TKI+局部治療多發病灶：WBRT+TKINCCN關于NSCLC腦轉移的治療NCCN關于NSCLC腦轉移的治療60感謝關注！Bhatt VR et al.2015 WCLC mini10.14Bhatt VR et al.2015 WCLC mini10.14非小細胞肺癌腦轉移情況及EGFR突變狀態的研究結論Villano JL,et al. Ann Oncol,2003,14:656-8.首例Gefibinib治療NSCLC腦轉移吉非替尼和厄洛替尼的CSF濃度和腦轉移灶緩解率對比Togashi et al. Cancer Chemother Pharmacol (2012) 70