1.ALK阳性非小细胞肺癌全程管理

首要研究终点ORR （研究者评估）： • 46% vs. 55%
15.6 (11.1–19.4)
HR = 0.64 (0.45–0.91)
0 0 6 12 18 Time (months) 24 30 36
ALTA-1L研究（III期，ALK初治 vs 克唑替尼）进行中
Ahn, et al. WCLC 2017
Driver oncogenes
Sacher et al., JAMA oncol, 2, 313-20 (2016)
ALK抑制剂问世前，化疗方案效果不好 ALK+患者的OS较短
Response rate to SOC
Chemo (Pt doublet) EGFR-TKI ALK+ (n=15) 25% 0% EGFRmt (n=25) 50% 70% WT/WT (n=49) 35% 13%
RET INSR KDR ROS1 ABL EGFR EGFR2 HER2 IGF1R JAK1 KIT MET PDFGRβ RON SRC AKT1 AuroraA CDK1 CDK2 MEK1 PKA PKCα PKCβ1 PKCβ2 Raf-1
ALK
RET INSR KDR ROS1 ABL EGFR EGFR2 HER2 IGF1R JAK1 KIT MET PDFGRβ RON SRC AKT1 AuroraA CDK1 CDK2 MEK1 PKA PKCα PKCβ1 PKCβ2 Raf-1
10.9
8.1
Ceritinib (ASCEND-5)2
5.4
16.6
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
*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 and data maturity
R
1:1
1.0 0.8 0.6
培美曲塞或多西他赛 i.v. q3w
PFS
5.4
塞瑞替尼 (n=115) 化疗 (n=116)
0.4 0.2
HR=0.49 (0.36–0.67)
p<0.001
0
1.6
0 6 时间 (月) 12 18 24
Shaw, et al. Lancet Oncol 2017
ASCEND-4: 塞瑞替尼对比化疗的三期临床研究
Diarrhoe a Nausea Vomiting ALT increase AST increase GGT increase
Time (months)
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
ALT = alanine transaminase; AST = aspartate transaminase; GGT = gammaglutamyltransferase; GI = gastro-intestinal
(Dec)
Alectinib EMA 1L approval
Crizotini b Alectinib Certinib Brigatinib
1.Dearden, et al. Ann Oncol 2013; 2. Gridelli, et al. Cancer 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.
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
PROFILE 1014: 克唑替尼对比化疗的三期临床研究
Efficacy 100
% of patients with AEs
Crizotinib (n=172) Chemotherapy (n=171) 0.6 HR=0.45 (95% CI: 0.35–0.60) p<0.001
目前FDA批准的所有ALK抑制剂临床研究结果
ALK
RET INSR KDR ROS1 ABL EGFR FGFR2 HER2 IGF1R JAK1 KIT MET PDFGRβ RON SRC AKT1 AKT2 AKT3 AuroraA CDK1 CDK2 MEK1 PKA PKCα PKCβ1 PKCβ2 Raf-1
ROS1
ROS1
细胞信号激酶
2014 (Jul)
Alectinib approved in Japan
2017 (Apr) 2016 (Sep)
FDA granted Alecensa 2nd BTD for 1L ALK+ NSCLC Brigatinib FDA Accelarate approval for ALKpositive NSCLC progressing on/or intolerant to crizitinib
% of patients with AEs
Chemotherapy (n=187)
Soria, et al. Lancet Oncol 2017
9
ALK+ NSCLC患者的1L治疗现状
PFS* 化疗 7.0 (PROFILE 10141)
克唑替尼 (PROFILE 10141)
化疗 (ASCEND-42) 塞瑞替尼 (ASCEND-42)
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
AE = adverse event; PFS = progression-free survival; GI = gastrointestinal; HR = hazard ratio
Solomon, et al. N Engl J Med 2014
IGF1R
高效选择性ALK抑制剂
MET
Crizotinib III期研究 CFDA适应症 PROFILE 1014、1029 克唑替尼优于化疗 2013年1月（全线）
Ceritinib ASCEND 4 Ceritinib优于化疗 2018年6月1日
Alectinib ALEX、J-ALEX Alectinib优于克唑替尼 2018年8月17日
Shaw et al. J. Clin. Oncol., 27, 4247-4253 (2009)
Lee et al. Cancer, 118, 3579-86 (2012)
ALK通路及药物发展简史
2011 (Aug)
2013 (Jun)
FDA granted Alectinib BTD for ALK+ NSCLC patients who have progressed on crizotinib
2017 (Feb)
Alectinib approved in EU (Crizotinib failure)
2017 (May)
Ceritinib FDA 1L approval
2017 (Nov)
Alectinib FDA 1L approval
2018 (Jun)
Ceritinib CFDA 2L approval
Certinib FDA approved for ALKpositive, crizotinib resistant NSCLC
2015 (Dec)
Alectinib FDA approval for ALK-positive NSCLC progressing on/or intolerant to crizitinib
指南推荐的一线治疗药物（NCCN 2018 v3）
Crizotinib
IC50 (nM) 10,000 1,000 100 10 1 IC50 (nM) 10,000
Ceritinib
1,000 100 10 1 IC50 (nM)
Alectinib
10,000 1,000 100 10 1
ALK
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
Genetic alterations in NSCLC
(DFCI: 2002~2014)
EGFR
Others Kinase domain
ALK (5%)
KRAS ROS1 BRAF V600E
Soda et al., Nature, 448, 561-6 (2007)
6
克唑替尼对比化疗的PFS
PFS*
化疗 (PROFILE 10141) 克唑替尼 (PROFILE 10141)
7.0
10.9
Median PFS (months)
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
Soc = Standard of care
Solomon, et al. N Engl J Med 2014
7
ASCEND-5: 塞瑞替尼治疗克唑失败之后的ALK+患者
• 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)
塞瑞替尼 750mg/day
三代ALK抑制剂发展之路
Crizotinib
Ceritinib
Alectini b
Brigatinib
促进ALK结合活性
脂溶性增加，促进CNS暴露
Lorlatinib
不同的酪氨酸激酶域结合模式
对ALK耐药突变的敏感性
对二代耐药突变有效
Kodama et al. Mol Cancer Ther (2014)
Efficacy
Safety
1.0 0.8 PFS estimate 0.6 0.4 0.2 0 0 3
Ceritinib (n=189)
HR=0.55 (95% CI: 0.42–0.73) Log-rank p<0.00001
8.1
6 9 12 15 18
16.6
21 24 27 30 33 36
2018 (Aug)
–ALK fusion discovered in NSCLC
Crizotinib, approved for advanced ALK+ NSCLC
2014 (Apr) 2013 (Jan) Crizotinib , approved in China
Safety
1.0
0.8
80 60 40 20 0
PFS probability
0.4
0.2
0 0
7.0
5
10.9
10 15 20 25 30 35 Time (months)
Vision disorder s
Diarrhoea
Oedema
Vomiting Constipation
AST increase d
Arm A Brigatinib 90mg QD* (n=112) Arm B Brigatinib 180mg QD§ (n=110)
100 Probability of PFS (%) 80 60 40 20
9.2 (7.4–11.1)
Brigatinib: 90mg QD (n=112) Brigatinib: 180mg QD* (n=110)
1. Solomon, et al. N Engl J Med 2014; 2. Soria, et al. Lancet Oncol 2017 4. Ferrara, et al. J Thorac. Oncol 2018
1
Brigatinib： 克唑替尼治疗失败患者的II期研究（ALTA）
• 局部晚期或转移性ALK+ NSCLC • 既往克唑替尼失败 • 脑转移患者可入组 • ECOG PS 0–2 (n=222) R 1:1