PFS probability % of patients with AEs
Efficacy
1.0
Crizotinib(n=172)
0.8
Chemotherapy(n=171)
HR=0.45(95%CI: 0.35–0.60)
0.6
p<0.000
5
10
15
20
25
30
35
crizotinib
2014 (Jul)
Alectinib
approved in Japan
2016 (Sep)
FDA granted
Alecensa 2nd BTD for 1L
ALK+ NSCLC
2017 (Apr)
Brigatinib FDA Accelarate
approval for ALKpositive NSCLC
Ceritinib
Alectinib
ASCEND 4
ALEX、J-ALEX
Ceritinib优于化疗
Alectinib优于克唑替尼
2018年6月1日（二线） 2018年8月17日（全线）
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:克唑替尼与化疗的比较
KIT MET
PDFGRβ RON SRC AKT1
AuroraA CDK1 CDK2 MEK1 PKA PKCα PKCβ1 PKCβ2 Raf-1
10
1
ROS1
MET
Ceritinib
IC50 (nM) 10,000
ALK RET
INSR KDR ROS1 ABL EGFR EGFR2 HER2 IGF1R JAK1
MET PDFGRβ
RON SRC AKT1 AKT2 AKT3 AuroraA CDK1 CDK2 MEK1 PKA PKCα PKCβ1 PKCβ2 Raf-1
100
10
1
高效选择性ALK抑制剂
III期研究 CFDA适应症
Crizotinib
PROFILE 1014、1029 克唑替尼优于化疗 2013年1月（全线）
ALK+非小细胞肺癌患者全程管理
ALK阳性晚期NSCLC
Kinasedomain
Sodaet al., Nature, 448,561-6(2007)
Driver oncogenes
ALK抑制剂问世前，传统治疗方案 ALK+患者的OS较短
Geneticalterationsin NSCLC
(DFCI: 2002~2014)
2007
EML4–ALK fusion
discovered in NSCLC
2011 (Aug)
Crizotinib, approved
for advanced
ALK+ NSCLC
2013 (Jun)
FDA granted Alectinib BTD
for ALK+ NSCLC patients
whohave progressedon
EGFR
Others
KRAS
ALK(5% ROS1 )
BRAF V600E
Sacheret al., JAMA oncol, 2, 313-20(2016)
Leeet al. Cancer,118, 3579-86(2012)
JAMA. 2014May 21;311(19):1998-2006.
ALK通路药物发展是精准医学的完美演绎
2018 (Jun)
Ceritinib
CFDA 2Lapproval
2018 (Nov)
Lorlatinib FDA 2L approval
1.Dearden, et al. Ann Oncol2013; 2. Gridelli, et al. CancerTreat Rev 2014 3. Hallberg, et al. Nat Rev Cancer2013; 4. Rikova, et al. Cell 2007; 5. Soda, et al. Nature 2007; 6. American Cancer Society 2013 7. Torre, et al. CA CancerJ Clin 2015; 8. Perez, et al. Lung Cancer; 9/Lancet. 2016 ;388(10048):1012-24.
progressingon/or intolerantto crizitinib
2018 (Aug)
Alectinib CFDA
approval
Crizotinib Alectinib
Certinib Brigatinib
2013 (Jan)
Crizotinib ,
approved in China
to crizitinib
2017 (Feb)
Alectinib approved
in EU (Crizotinib
failure)
2017 (May)
Ceritinib FDA 1L approval
2017 (Nov)
AlectinibFDA 1Lapproval
(Dec)
AlectinibEMA 1Lapproval
Time (months)
Safety
100
80
60
KIT MET
1,000
PDFGRβ RON SRC AKT1
AuroraA CDK1 CDK2 MEK1 PKA PKCα PKCβ1 PKCβ2 Raf-1
100
10
1
ROS1 IGF1R
Alectinib
IC50 (nM) 10,000 1,000
ALK RET
INSR KDR ROS1 ABL EGFR FGFR2 HER2 IGF1R JAK1 KIT
2014 (Apr)
Certinib FDA
approved for ALKpositive, crizotinib resistant NSCLC
2015
(Dec)
AlectinibFDA approval for
ALK-positive NSCLC
progressing on/or intolerant
1
ALK+患者一线治疗的优化
2
一线耐药后的治疗现状
3
ALK-TKI的耐药机制及后续治疗
指南推荐的一线治疗药物（NCCN 2018 v3）
细胞信号激酶
Crizotinib
IC50 (nM) 10,000 1,000 100
ALK RET
INSR KDR ROS1 ABL EGFR EGFR2 HER2 IGF1R JAK1