30日上午肺癌精准诊疗研讨会3

1、NSCLC靶向治疗如何精益求精范 云浙江省肿瘤医院胸部肿瘤内科 P-AVS-2016.12-031 Valid Until 2018.122016NSCLC脑转移治疗新进展浙江省肿瘤医院胸部肿瘤内科 范云2016-12-30 福州NSCLC脑转移发生率高: EGFR突变或ALK+发生率更高ALK, anaplastic lymphoma kinase; BM, brain metastases; CNS, central nervous system; EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung canc

2、er; TKI, tyrosine kinase inhibitor.1. Srensen JB, et al. J Clin Oncol 1988;6:147480; 2. Dempke W, et al. Anticancer Res 2015;35:5797806; 3. Omuro AMP, et al. Cancer 2005;103:23448; 4. Heon S, et al. Clin Cancer Res 2010;16:587382; 5. Lee YJ, et al. Cancer 2010:116;133643; 6. Shaw AT, et al. Lancet O

3、ncol 2011;12:100412; 7. Camidge DR, et al. Nat Rev Clin Oncol 2014;11:47381; data presented at ASCO 2015, by Soria J-C.BM 30%(2540%)BM 40%(3060%)BM 50%驱动基因阳性患者BM发生率高的可能原因:不同生物学特性药物血脑屏障穿透率不高生存期长NSCLC脑转移的治疗观念逐渐在转变1、脑转移的分类问题：有无症状是否有基因突变EGFR突变还是ALK+？TKI治疗前还是耐药后3、局部治疗方式的选择：是否需要局部治疗？SRS vs SRS+WBRT？2、药物治疗

4、的发展：TKI的疗效与选择不同靶点的治疗差异4、脑转移的综合治疗：局部治疗时机的选择新药的研发脑转移的预防？新的预后模型？驱动基因阳性脑转移患者的治疗+TKIs 治疗局部治疗TKIs 的疗效？TKI耐药后治疗？局部治疗方式的选择？局部治疗时机的选择？有待解决的问题？Q1：EGFR TKI治疗脑转移的疗效？EGFR-TKI在脑脊液中的浓度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. M

5、asuda T,et al.Cancer Chemo Pharm,2011,67:1465-1469; 4. Togashi Y,et al.J Thorac Oncol,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 7608. 7.Fan Yun. Cancer Chemother Pharmacol (2015) 76:517523. 8.Lung

6、cancer2016 Jun;96:939.Tamiya et al.Ann Oncol.20161.日本京都大学医学院 2.美国田纳西州儿童医院 3.日本仙台东北大学 4.美国波士顿医院 5.哈佛医学院 6.北京协和医院 7.浙江省肿瘤医院 8.华西医院1.4%1.65%阿法替尼9不同EGFR TKI脑脊液/血浆浓度比TKI治疗EGFR敏感突变NSCLC脑转移研究项目期别药物N治疗方法ORR (%)sPFS（月）OS（月）CTONG0803II厄洛替尼8/48单药100%/50%15.218.9日本II吉非替尼41单药87.8%14.521.9中国II埃克替尼10/20+WBRT90.0%1

7、2.022.0中国I埃克替尼15+WBRT80.0%18.9NRLux-Lung3&6III亚组阿法替尼81单药8.222.4Ann Oncol.2013 Apr;24(4):993-9T. luchi, et al.Lung Cancer,82(2013)282-287Fan Yun. Cancer Chemother Pharmacol (2015) 76:517523J Thorac Oncol, 2016 Mar;11(3):380-90BRAIN: 埃克替尼对比WBI加化疗在EGFR突变的晚期NSCLC脑转移的一项期临床研究(CTONG 1201)iPFSPFSOSORR（颅内）月P

8、月P月P%P埃克替尼（N=85）10.0.0016.8.00118.0.73467.2.014WBRT化疗（N=73）4.83.420.540.9结论：埃克替尼应该作为EGFR突变的晚期NSCLC伴随脑转 移的一线治疗Q2：一代EGFR TKI耐药后治疗？新药进展：血脑屏障穿透率较高的EGFR抑制剂OsimertinibAZD3759结构嘧啶喹唑啉是否抑制T790M?YesNo剂量80mg 已批准20-240mg 测试中50-500mg血脑屏障透过率：临床前模型Kpuu，brain =0.391Kpuu，brain =1.33血脑屏障透过率：病例报道Kpuu，CSF =0.52Kpuu，CSF

9、 =1.04Presented By Pasi Janne at 2016 ASCO Annual Meeting吉非替尼Kpuu，brain =0.021Kpuu =脑脊液/血浆游离药物浓度比值BLOOM研究设计I期研究，评估AZD3759或奥希替尼在EGFR突变进展期NSCLC患者中的安全性、可耐受性、药代动力学、初步抗肿瘤疗效剂量扩展阶段软脑膜转移未经EGFR-TKI治疗或因颅外稳定病灶曾EGFR-TKI治疗脑转移未经EGFR-TKI治疗奥希替尼 160mg QDNSCLC LM 曾EGFR-TKI治疗Cohort 1：EGFRm NSCLC LM，有颅外稳定病灶，N=21（最新报告）C

10、ohort 2：T790M+ NSCLC LM，无论是否有颅外稳定病灶，N=20（仍在入组）Presented by: James Yang. Abs 9002 ASCO 2016.结论： AZD3759和奥希替尼对EGFR突变脑膜转移患者有效13奥西替尼治疗T790M突变阳性患者：中枢神经系统的疗效两项II期研究的Pool分析CNS ORR 54%12个月的CNS 无进展率56%CNS 病灶的ORR 54% ，DCR 92%，起效快（6周内）是否放疗的患者均能观察到疗效颅内PFS数据不成熟，初步观察前景喜人15AURA3研究：基线伴/不伴脑转移患者的PFS获益Population: inte

11、nt-to-treatProgression-free survival defined as time from randomisation until date of objective disease progression or death. Progression included deaths in the absence of RECIST progression.Tick marks indicate censored data. CNS metastases determined programmatically from baseline data of CNS lesio

12、n site, medical history, and/or surgery, and/or radiotherapy. 2016 WCLCPL03.03 V. Papadimitrakopoulou Pembrolizumab治疗NSCLC和黑色素瘤脑转移的II期研究2014-2015年筛选52例患者18 例黑色素瘤18例 NSCLC黑色素瘤 ORR 22%（95% CI 748）NSCLC ORR 33% （95% 1459)Pembrolizumab在脑转移患者显示出活性Lancet Oncol 2016; 17: 97683NSCLC， ORR 33%黑色素瘤， ORR 22%黑色素

13、瘤非小细胞肺癌OAK研究：CNS转移亚组疗效（ Atezolizumab对比多西他塞）虽然两组出现CNS新病灶发生率相似，但Atezolizumab组出现CNS新病灶的时间更晚CNS转移患者中， Atezolizumab治疗未见其他不良反应CNS转移无CNS转移ITT120.2HR多西他赛更佳Atezolizumab更佳TC3或IC3TC1/2/3或IC1/2/3*TC0和IC0CNS转移Atezo(N=38)Doc(N=47)Atezo(N=387)Doc(N=378)无CNS转移0%20%40%60%80%100%PD-L1表达Gadgeel S, et al. 2016 WCLC Abs

14、tract PL04A.02.*TC1/2/3或IC1/2/3包括TC3或IC3OS HRPFS HR0.540.750.730.610.970.93Q3：ALK抑制剂治疗脑转移？S.Peters, ESMO 2016ALK+ NSCLC的发生率ALK+ NSCLC的脑转移发生率Discussion MA07.03 07.02 & 07.01 Benjamin BesseALK+ NSCLC：脑转移的发生率Presentation Number: Presentation Title Presenting AuthorSeto Lancet 2013; 2. Shaw Lancet 2016;

15、 3. Ou J Clin Oncol 2016; 4. Nokihara ASCO 2016; 5. Kim Lancet 2016; 6. Crino J Clin Oncol 2016, 7. Felip ASCO 2016, 8. Camidge, WCLC 2016; 9. Solomon ASCO 2016; 10: Drilon ACCR 2016 Next Gen. ALK TKIDrugStudyPhaseNEfficacyMedian FUORRn (%)mPFS (months)ALECTINIB (RO5424802)AF-002JGNP28761NP28673J-AL

16、EX*I/IIIIIIIII446912210355%48%50%-NA8.18.9-4.24.8NANACERITINIB(LDK378)ASCEND-1ASCEND-2ASCEND-3IIIII16314012456.4%38.6%63.7%6.95.711.111.111.3NABRIGATINIB(AP26113)ALTA 90mgALTA 180mgIIII10911049%54%9.215.610.211LORLATINIB(PF-06463922)NCT01970865I/II4146%11.4NAENTRECTINIB(RXDX-101)NTC02097810I/II757%N

17、ANA克唑替尼的耐药机制及下一代的ALK抑制剂Presentation Number: Presentation Title Presenting AuthorNA: non available* only Japanese population1. Seto Lancet 2013; 2. Gadgeel Lancet 2014; 3. Shaw Lancet 2016; 4. Ou J Clin Oncol 2016; 5. Nokihara ASCO 2016Alectinib 治疗ALK+ NSCLC的研究及疗效NP28761 + NP28673 Alectinib 600mg BID

18、 Measurable and non-measurableCNS disease (n=136)CNS ORR, % (95% CI)44.1 (35.652.9)Complete response, n (%)39 (28.7)Partial response, n (%)21 (15.4)Stable disease, n (%)57 (41.9)Progressive disease, n (%)12 (8.8)CNS DCR, % (95% CI)86.0 (79.191.4)Median CNS DOR, months (95% CI)13.8 (11.021.5)Discussi

19、on MA07.03 07.02 & 07.01 。Benjamin BesseAlectinib 治疗ALK+ NSCLC：两项研究的Pooled分析 （中枢神经系统病灶的疗效评介）无脑转移脑转移100806040200PFS rate (%)06121827242139151AlectinibCrizotinibTime (months)No. of patients at risk402822126348281653806389758974100806040200PFS rate (%)06121827242139151AlectinibCrizotinibTime (months)No

20、. of patients at risk91252131785411323142914281Alectinib (N=89)Crizotinib (N=75)Event24 (27.0%)42 (56.0%)Median 95% CI20.3 17.5 ; -10.0 8.2 ; 13.9P-Value0.0001HR 95% CI*0.37 0.22 ; 0.62Alectinib (N=14)Crizotinib (N=29)Event1 (7.1%)16 (55.2%)Median 95% CI- - ; -10.2 6.5 ; 14.2P-Value0.0062HR 95% CI*0

21、.09 0.01 ; 0.74AlectinibCrizotinibAlectinibCrizotinibPresentation Number: Presentation Title Presenting AuthorPresentation Number: 5597 Primary Results from Phase III Study (J-ALEX) - Young Hak Kim* StratifiedJ-ALEX - PFS 基线时患者有或者没有脑转移J-ALEX（ Alectinib对比克唑替尼）研究：脑转移患者的亚组分析OA08.06: Brigatinib Activity

22、 in Patients With ALK+ NSCLC and Intracranial CNS MetastasesScott N GettingerBest Change From Baseline in Target Lesions (%)2040608010002040ALTA, Arm A 90 mg qdConfirmed partial responseConfirmed complete responseProgressive diseaseStable diseasecALTA, Arm B90 mg 180 mg qdb20406080100020402040608010

23、002040Phase 1/2aaLast scan date: 8 October 2015 (phase 1/2), 13 July 2016 (ALTA); dotted line at 30% indicates threshold for partial response per RECIST v1.1a Crizotinib-naive patients (n=2); b 180 mg qd with 7-d lead-in at 90 mg; c Includes single responses not confirmedORR：Brigatinib治疗脑转移的疗效Confir

24、med ORR, n (%)8 (53)Confirmed ORR, n (%)12 (46)Confirmed ORR, n (%)12 (67)Brigatinib治疗ALK+的临床研究（脑转移亚组）OA08.06: Brigatinib Activity in Patients With ALK+ NSCLC and Intracranial CNS MetastasesScott N GettingerPhase 1/2ALTAMedian Intracranial PFS (95% CI)Any MetastasesActive MetastasesArm A: 90 mg qd15

25、.6 mo(9.018.3)15.6 mo(12.718.3)Arm B: 90 mg 180 mg qda18.4 mo(12.8not reached)18.4 mo(11.0not reached)Last scan date: 13 July 2016; a 180 mg qd with 7-d lead-in at 90 mg Median Intracranial PFS (95% CI)All evaluable14.6 mo(12.736.8)No prior brain radiotherapy12.9 mo(9.0not reached)Last scan date: 8

26、October 2015Intracranial PFS ：Brigatinib Brigatinib治疗ALK+：颅内病灶的PFS色瑞替尼治疗ALK+NSCLC：ASCEND-4研究及亚组分析PL03: First-line ceritinib vs chemotherapy (ASCEND-4) G de Castro et alALK TKI : Brain Mets Efficacy1. Costa J Clin Oncol 2015; 2. Solomon N England J Med 2014; 3. Kim Lancet 2016; 4. Crino J Clin Oncol

27、2016, 5. Felip ASCO 2016, Gettinger Lancet 2016 CRIZOTINIBCERITINIBBRIGATINIBDiscussion MA07.03 07.02 & 07.01 Benjamin BesseALK抑制剂治疗脑转移的疗效+ ON STUDYBRIGATINIBLORLATINIBENTRECTINIBALK+ NSCLC脑转移的治疗及疗效Johung JCO 2016CHEMORTALK TKICRIZOTINIBALECTINIBCERITINIBWBRTSRS培美曲赛联合铂类MEDIAN OS 49.5 MONTHSDiscussio

28、n MA07.03 07.02 & 07.01 Benjamin BesseQ4：局部治疗方式的选择？NSCLC脑转移瘤局部治疗方式回顾90WBRT临床分层902009SRS/WWBRT手术+W/S寡SRSWBRT多1.Gaspar L, et al. . Int. J. Radiation Oncology Biol. Phys 37, 745-751, 1997。2. Leibel SA Textbook of Radiation Oncology, p293-323, 1998.3. Li J, et al. J Clin Oncol 2007; 25:1260-1266. 4. And

29、rews DW, et al. Lancet 2004; 363(9422):1665-1672.SRS比较SRS+WBRT治疗NSCLC脑转移的随机对照研究SRS+WBRT 对比 SRS，随机研究结果：提高颅内病灶的局部控制率（更好的局控率及更少的新发病灶）未改善总生存N0574研究：比较SRS 与 SRS+WBRTJAMA July 26, 2016 Volume 316, Number 4SRS SRS+WBRT P值3个月时的认知障碍 (95% CI)63.5% (50.5, 75.3)91.7% (80.0, 97.7)0.0007认知测验SRS (%)SRS+WBRT (%)P值H

30、VLT 总记忆8.230.40.0043HVLT 延迟记忆19.751.10.0009HVLT 识别22.640.40.0585TMT A部分16.730.40.1063TMT B部分19.037.20.0677COWA1.918.60.0098凹槽拼板测验29.347.70.0656神经心理测验量表：HVLT霍普金斯语词学习测验 TMT连线测验，COWA词汇联想测验(语言流畅能力）对于1-3个脑转移患者（肺癌占比72% vs 65%）：判断治疗3个月后SRS组患者的认知障碍是否少于SRS+WBRT组 SRS+WBRT的认知功能恶化更多，并持续到6个月77.8% vs. 97.9% P=0.0

31、32N0574研究：比较SRS 与 SRS+WBRT3、6和12个 月的颅内病灶复发率(P .001)SRS + WBRT ：6.3%、11.6%、15.0% SRS单独治疗： 24.7%、 35.3%、 49.5% 中位生存时间：SRS+WBRT vs SRS7.4 vs 10.4个月（P=0.92）JAMA July 26, 2016 Volume 316, Number 4NCCTG N0574研究：结论JAMA July 26, 2016 Volume 316, Number 4对于1-3个脑部转移灶患者：SRS+WBRT不改善生存，SRS+WBRT导致患者3个月时的认知功能下降，影响生活质量对这些患者，单纯SRS是可行的治疗方法SRS单独应用可能是一种可行的治疗策略NSCLC脑转移手术后放疗研究NSCLC脑转移手术后，比较 SRS 与 观察组（N=131） SRS组与观察组的6个月的局控率分别为84% vs 57%（P=0.011） SRS组与观察组的OS均为17个月（P=0.37）手术后SRS提高局控率，未改善OS NS