1、,不一样的时代 ALK+非小细胞肺癌患者全程管理,ALK阳性晚期NSCLC,Soda et al., Nature, 448, 561-6 (2007),Lee et al. Cancer, 118, 3579-86 (2012),Shaw et al. J. Clin. Oncol., 27, 4247-4253 (2009),Driver oncogenes,Kinase domain,ALK抑制剂问世前，化疗方案效果不好 ALK+患者的OS较短,ALK通路及药物发展简史,1.Dearden, et al. Ann Oncol 2013; 2. Gridelli, et al. Cance
2、r Treat Rev 2014 3. Hallberg, et al. Nat Rev Cancer 2013; 4. Rikova, et al. Cell 2007; 5. Soda, et al. Nature 2007; 6. American Cancer Society 2013 7. Torre, et al. CA Cancer J Clin 2015; 8. Perez, et al. Lung Cancer; 9/Lancet. 2016 ;388(10048):1012-24.,2011 (Aug)Crizotinib, approved for advanced AL
3、K+ NSCLC,2014 (Jul) Alectinib approved in Japan,2013 (Jun) FDA granted Alectinib BTD for ALK+ NSCLC patients who have progressed on crizotinib,2007 EML4ALK fusion discovered in NSCLC,2015 (Dec) Alectinib FDA approval for ALK-positive NSCLC progressing on/or intolerant to crizitinib,2016 (Sep) FDA gr
4、anted Alecensa 2nd BTD for 1L ALK+ NSCLC,2017 (Feb) Alectinib approved in EU (Crizotinib failure),2017 (May) Ceritinib FDA 1L approval,2014 (Apr) Certinib FDA approved for ALK-positive, crizotinib resistant NSCLC,Crizotinib,Alectinib,Certinib,2017 (Nov) Alectinib FDA 1L approval (Dec) Alectinib EMA
5、1L approval,2018 (Jun) Ceritinib CFDA 2L approval,2013 (Jan) Crizotinib, approved in China,2017 (Apr) Brigatinib FDA Accelarate approval for ALK-positive NSCLC progressing on/or intolerant to crizitinib,Brigatinib,2018 (Aug) Alectinib CFDA approval,三代ALK抑制剂发展之路,Ceritinib,Crizotinib,不同的酪氨酸激酶域结合模式 对AL
6、K耐药突变的敏感性,Alectinib,Kodama et al. Mol Cancer Ther (2014),Lorlatinib,促进ALK结合活性,脂溶性增加，促进CNS暴露,对二代耐药突变有效,Brigatinib,指南推荐的一线治疗药物（NCCN 2018 v3）,细胞信号激酶,首个在头对头III期研究中证实优于另一种TKI药物的靶向治疗药物,高效选择性ALK抑制剂,PROFILE 1014: 克唑替尼对比化疗的三期临床研究,AE = adverse event; PFS = progression-free survival; GI = gastrointestinal; HR
7、= hazard ratio,Solomon, et al. N Engl J Med 2014,6,PFS probability,Time (months),10,20,30,5,15,25,7.0,10.9,0.8,0.6,0.4,0.2,0,1.0,0,35,Efficacy,与化疗相比，克唑替尼表现出了高有效性和安全性， 视觉障碍和消化道的副反应是克唑替尼最常见的AEs,Vision disorders,Diarrhoea,Oedema,Vomiting,Constipation,AST increased,Safety,% of patients with AEs,克唑替尼对比化疗
8、的PFS,Soc = Standard of care,Solomon, et al. N Engl J Med 2014,7,Median PFS (months),克唑替尼 (PROFILE 10141),化疗 (PROFILE 10141),7.0,10.9,PFS*,克唑替尼通过PROFILE1014的研究成功取代了化疗，成为ALK阳性非小细胞肺癌一线标准治疗方案,塞瑞替尼 (n=115) 化疗 (n=116),HR=0.49 (0.360.67) p0.001,ASCEND-5: 塞瑞替尼治疗克唑失败之后的ALK+患者,1.0,0.8,0.6,0.4,0.2,0,0,时间 (月),P
9、FS,24,6,12,18,1.6,Shaw, et al. Lancet Oncol 2017,培美曲塞或多西他赛 i.v. q3w,R,1:1,塞瑞替尼 750mg/day,IIIB/IV期NSCLC FISH检测ALK+ 曾接受过克唑替尼和含铂双药方案治疗) 据RECIST 1.1标准，1个可测量病灶 (n=236),5.4,ASCEND-4: 塞瑞替尼对比化疗的三期临床研究,ALT = alanine transaminase; AST = aspartate transaminase; GGT = gamma-glutamyltransferase; GI = gastro-inte
10、stinal,Soria, et al. Lancet Oncol 2017,9,Ceritinib (n=189) Chemotherapy (n=187),HR=0.55 (95% CI: 0.420.73) Log-rank p0.00001,1.0,0.8,0.6,0.4,0.2,0,0,Time (months),PFS estimate,9,6,18,24,33,15,21,30,3,12,27,16.6,8.1,36,Efficacy,塞瑞替尼相比化疗同样表现出了非常好的疗效 但是塞瑞替尼具有较高的胃肠道副反应以及较强的肝毒性,Safety,Diarrhoea,Nausea,Vo
11、miting,ALT increase,AST increase,GGT increase,% of patients with AEs,ALK+ NSCLC患者的1L治疗现状,*Adapted and updated from Ferrera et al, 20183. For illustration purposes only; note that cross-trial comparisons should be interpreted with caution due to differences in study design, size, patient population a
12、nd data maturity,1. Solomon, et al. N Engl J Med 2014; 2. Soria, et al. Lancet Oncol 2017 4. Ferrara, et al. J Thorac. Oncol 2018,10,克唑替尼 (PROFILE 10141),塞瑞替尼 (ASCEND-42),Median PFS (months),塞瑞替尼为ALK+NSCLC提供了另一个一线治疗的可选方案 塞瑞替尼在与化疗的对比的临床研究中体现出了更长的PFS值,化疗 (PROFILE 10141),7.0,化疗 (ASCEND-42),8.1,10.9,16.
13、6,PFS*,Ceritinib (ASCEND-5)2,5.4,Brigatinib： 克唑替尼治疗失败患者的II期研究（ALTA）,首要研究终点ORR（研究者评估）： 46% vs. 55%,ALTA-1L研究（III期，ALK初治 vs 克唑替尼）进行中,Ahn, et al. WCLC 2017,目前FDA批准的所有ALK抑制剂临床研究结果,*Adapted and updated from Ferrera et al, 20187. For illustration purposes only; note that cross-trial comparisons should be
14、interpreted with caution due to differences in study design, size, patient population and data maturity NR = not reached * Brigatinib not yet apprioved in EU,1. Solomon, et al. N Eng J Med 2014; 2. Shaw, et al. Lancet 2017 3. Novello, et al. Ann Oncol 2018; 4.Huber, et al. ASCO 2018 5. Soria, et al.
15、 Lancet Oncol 2017; 6. Camidge, et al. ASCO 2018 7. Ferrara, et al. J Thorac. Oncol 2018,12,PFS: 1L ALKi,PFS: 2L ALKi,Crizotinib (PROFILE 10141),塞瑞替尼 (ASCEND-45),16.6,Median PFS (months),5.4,Ceritinib (ASCEND-5)2,Brigatinib已经在ALKTKI的二线治疗中体现出了非常好的疗效 一线治疗的效果值得期待,化疗 (PROFILE 10141),7.0,ALK+NSCLC患者有更多切实
16、的需求,13,阿来替尼是否能给患者更多。,.更高的有效率,.更好的安全性 和耐受性,.对于脑转移病灶 更好的疗效,ALEX 研究 阿来替尼对比克唑替尼III期临床研究,主要终点 PFS（研究者评估）,1,2,分层因素 基线是否存在CNS转移（是 vs 否） 亚裔 vs 非亚裔 ECOG (01 vs 2),*孤立性无症状性CNS进展患者，允许继续治疗至出现全身性或症状性CNS进展 BID = 每天两次; DoR = 缓解持续时间 IHC = 免疫组化; IRC 独立评审委员会; ORR = 客观缓解率; OS = 总生存期 Peters, et al. N Engl J Med 2017,疗效
17、突破 阿来替尼中位PFS达到空前的34.8个月，且显著降低进展风险达57%,34.8 (17.7NE),10.9 (9.112.9),0,20,40,60,80,100,0,6,12,18,24,30,36,时间（月）,预估PFS (%),数据截至 2017.12.1,进展风险降低 57%,HR=0.43 (95%CI 0.32-0.58),INV,主要终点：PFS,数据截止日期：2017年12月1日 NE：不可评估 Takiguchi, et al. ASCO 2017； Peters et al, NEJM 2017 Camidge, et al. ASCO 2018 Poster num
18、ber: 9043,ALEX研究：阿来替尼缓解率达82.9%，且有效患者肿瘤缓解深度更深,疗效突破 阿来替尼缓解率更高，且缓解深度更佳,阿来替尼,克唑替尼,Camidge DR, et al. 2018 ASCO Abstract 9043.,阿来替尼在驱动基因阳性NSCLC的PFS创造了一个新的高峰,20,目前FDA批准的所有ALK抑制剂临床研究结果,*Adapted and updated from Ferrera et al, 20187. For illustration purposes only; note that cross-trial comparisons should b
19、e interpreted with caution due to differences in study design, size, patient population and data maturity NR = not reached * Brigatinib not yet apprioved in EU,1. Solomon, et al. N Eng J Med 2014; 2. Shaw, et al. Lancet 2017 3. Novello, et al. Ann Oncol 2018; 4.Huber, et al. ASCO 2018 5. Soria, et a
20、l. Lancet Oncol 2017; 6. Camidge, et al. ASCO 2018 7. Ferrara, et al. J Thorac. Oncol 2018,18,PFS: 1L ALKi,PFS: 2L ALKi,Crizotinib (PROFILE 10141),Ceritinib (ASCEND-45),16.6,Alectinib (ALEX6),34.8,Median PFS (months),5.4,Ceritinib (ASCEND-5 )2,Note: cross-trial comparisons should be interpreted with
21、 caution due to differences in study design, size, patient population and data maturityALEX 是第一个ALK靶向药物头对头的三期临床研究,ALEX临床研究很好的证明了ALK+NSCLC一线治疗最优选方案是阿来替尼,指南推荐 阿来替尼是NCCN指南中标注“优选”的一线治疗方案,NCCN Guidelines. Non-Small Cell Lung Cancer v4. 2018.,NCCN指南中对于ALK阳性非小细胞肺癌的指导,PD = disease progression; PD-L1 = progr
22、ammed death ligand 1,NCCN NSCLC guidelines V5.2018,20,NCCN 指南已经明确指出，在对于ALK+的晚期非小细胞肺癌患者一线治疗，阿来替尼是一线最优选方案 二线治疗方案需要根据进展模式进行换药,or,Consider local therapy,Continue 1L ALKi,Start 2L ALKi(only after crizotinib failure),or standard initial cytotoxic therapy options for NSCLC with no actionable biomarker,Star
23、t 2L ALKi (only after crizotinib failure),ALK+ NSCLC,PD,1L ALKi Alectinib (preferred) crizotinib ceritinib,Asymptomatic,Symptomatic brain metastases,Isolated symptomatic systemic lesion,Multiple symptomatic systemic lesions,1L ALKi,2L ALKi ceritinib alectinib brigatinib,Consider local therapy,Contin
24、ue 1L ALKi,不同ALK抑制剂在不同线数使用的有效率的差异,Brigatinib not yet approved in EU,1. Solomon, et al. N Engl J Med 2014; 2. Soria, et al. Lancet Oncol 2017; 3. Camidge, et al. ASCO 2018 4. Shaw, et al. Lancet Oncol 2017; 5. Novello, et al. Ann Oncol 2018 6. Yang, et al. J Thorac Oncol 2017; 7. Ahn, et al. WCLC 201
25、7; 8. Solomon, et al. WCLC 2017,21,10.9,1L,2L,3L,Response rate,Line of therapy,Emerging agent trials ongoing8,在一线治疗的时候ALK TKI药物的有效率是最高的克唑替尼、塞瑞替尼、阿来替尼三个药物一线治疗的基本相同，但是缓解时间差别非常大 如何把最合适的药物用在最合适的线数？才能让患者最大的获益,三代ALK TKI: 耐药后治疗是全程管理必须考虑内容三代齐发，如何排兵布阵？,三代ALK抑制剂Lorlatinib可能克服所有单一ALK突变耐药,Lorlatinib的临床可及剂量可抑制几乎
26、所有单一ALK突变,Cancer Discov. 2018 Jun;8(6):714-729.,Lorlatinib耐药克隆中出现的突变均为复合突变,三代ALK抑制剂Lorlatinib治疗ALK+ NSCLC PhaseII （多亚组）,Solomon, et al. WCLC 2017,主要临床终点 ORR 颅内ORR DLTs,*Patients in EXP6 were ROS1+ Abbreviations in slide notes,Solomen BJ, et al. WCLC 2017,Lorlatinib 治疗ALK+NSCLC：phase II 初治队列,Best Cha
27、nge From Baseline (%),37 patients (63%) had brain metastases at baseline.,Off treatment or PD occurred,Complete response,Partial response,Stable disease,Progressive disease (PD),CI, confidence interval; CT, chemotherapy; DOR, duration of response; mo, months; NR, not reached.,Lorlatinib 治疗ALK+NSCLC：
28、 EXP2 EXP3A EXP3B,经克唑治疗组,12 patients (44%) had brain metastases at baseline.,ORR 33%,经非克唑的ALK抑制剂治疗组,Intracraniala,b,Solomen BJ, et al. WCLC 2017,83 patients (75%) had brain metastases at baseline.,Off treatment or PD occurred,Complete response,Partial response,Stable disease,Progressive disease (PD)
29、,Indeterminate,CI, confidence interval; CT, chemotherapy; DOR, duration of response; mo, months; NR, not reached.,Lorlatinib 治疗ALK+NSCLC：EXP4+5,ORR 39%,经两种以上ALK抑制剂治疗组,Solomen BJ, et al. WCLC 2017,PFS: 1L ALKi,PFS: 2L ALKi,克唑替尼 (PROFILE 10141),10.9,塞瑞替尼 (ASCEND-5)2,5.4,9.6,10.9,Brigatinib* (ALTA-2)4,
30、15.6,塞瑞替尼 (ASCEND-45),16.6,阿来替尼 (ALEX6),34.8,Lorlatinib 2L,ALK抑制剂发展让肺癌走向慢性病管理时代,？,克唑替尼 PROFILE1014,克唑替尼 PROFILE1014,化疗 (PROFILE 1014 ASCEND-4)1,2,7.0-8.1,1. Solomon, et al. N Eng J Med 2014; 2. Shaw, et al. Lancet 2017 3. Novello, et al. Ann Oncol 2018; 4.Huber, et al. ASCO 2018 5. Soria, et al. Lan
31、cet Oncol 2017; 6. Camidge, et al. ASCO 2018 7. Ferrara, et al. J Thorac. Oncol 2018,总结,CNS = central nervous system; PFS = progression free survival; SoC = standard of care,1. Camidge, et al. ASCO 2018; 2. Peters, et al. New Engl J Med 2017,29,在NCCN指南当中，阿来替尼成为ALK+NSCLC患者一线治疗优选的方案有以下几个原因。,.它拥有最长的一线PFS (34.8 months1),拥有非常好的耐受性，和长时间用药的安全性,.不仅可以控制脑部病灶的进展，同时还能推迟脑部病灶的发生时间,感谢聆听！,
