PDGFRA
CCND1 DDR2
Amplification/Mutation
Amplification Mutation
9%
8% 4%
BRAF
ERBB2 FGFR2
Mutation
Amplification Mutation
4%
4% 3%
Govindan R et al. ASCO 2012
第一个有临床意义的NSCLC驱动基因：
Significantly Mutated Genes in Squamous Cell Lung Cancer
178/500鳞癌完成分析
Govindan et al. The Cancer Genome Atlas (TCGA) Project . 2012 ASCO
Therapeutic targets in squamous cell lung carcinoma
HER2
Large cell carcinoma
*Incidence of mutations in adenocarcinoma provided as an example
Current Standard of NSCLC Care
2
Figure: Massachusetts General Hospital, data on file. Horn L, Pao W. J Clin Oncol. 2009;26:4232–4235.
NSCLC肿瘤驱动基因
2010：7类肿瘤驱动基因，未知55% 2011：10类肿瘤驱动基因，未知46%
K-ras EGFR B-raf Her2 PIK3CA ALK MET Unknown
Unknown
Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01. Massachusetts General Hospital, data on file; Horn L, Pao W. J Clin Oncol 2009; 26:4232–4235.
Gene
CDKN2A PI3KCA PTEN FGFR1 EGFR
Event Type
Deletion/Mutation/Methylation Mutation Mutation/Deletion Amplification Amplification
Frequency
72% 16% 15% 15% 9%
6
151 134
8
114 79
10
93 51
Patients remaining Erlotinib Placebo 226 225
12 14 16 18 Time (months)
76 35 59 19 43 12 29 7
20
14 3
22
3 1
24
1 1
26
1 1
28
0 0
Mok, Wu et al. ASCO 2012
An SJ, Wu YL. PLoS One June 2012
91%抗肿瘤药物的敏感性与基因变异相关
分析了130种抗肿瘤 药物与肿瘤基因变异 之间的关系，证实 91% (118/130)的抗 肿瘤药物敏感性与至 少一种基因变异相关
Garnett MJ, et al. Nature 2012; 483:570-577.
Primary endpoint: PFS with IRC confirmation
NSCLC = non-small cell lung cancer; PS = performance status; PD = disease progression; AUC = area under the curve; q4wks = every 4 weeks; IRC = independent review committee; OS = overall survival; ORR = objective response rate; TTP = time to progression; NPR = non-progression rate; QoL = quality of life
13.7 10.4
4.6 5.4
0.16 p<0.0001 0.47 p<0.0001
22.7 19.3
28.8 19.5
1.04(0.69-1.58) 1.04(0.65-1.68)#
Afatinib trial
LUX-LUNG- 3 N=345 13.6 6.9 0.47 p<0.0001
FASTACT-2 (MO22201; CTONG0902) study design
OS
化疗组 HR
NEJ0022 N=194
WJTOG34053 N=172 Erlotinib trials OPTIMAL4 N= 154 EURTAC5 N=174
10.8
9.2
5.4
6.3
0.36 P<0.001
0.49 P<0.0001
27.7
36
26.6
39
0.89(0.63-1.24)
1.19(0.77-1.83)
Mok, ESMO 2012
OS in ITT population (22 Jun 2012)
1.0 0.8 OS probability 0.6 0.4
Erlotinib (n=226)
Placebo (n=225)
HR=0.79 (95% CI 0.64–0.99) p=0.0420
0.2
0 0
Erlotinib (n=20) Placebo (n=17) HR=0.55 (0.27–1.12) p=0.0941
OS
1.0 0.8
Erlotinib (n=20) Placebo (n=17) HR=0.32 (0.14–0.69) p=0.0024
PFS probability
0.6
0.4 0.2 0 0 4.6 7.5 4 8 12 16 20 24 28
PFS probability
0.6
0.4 0.2 0 0 6.9 4 8 16.8 12 16 20 24 28 32
OS probability
0.6
0.4 0.2 0b 0 4 8 20.6 31.4
12 16 20 24 28 32 36
Time (months)
E P 49 48 46 35 42 16 33 5 25 4 19 2 11 2 6 1 0 0 E P 49 48 48 48 46 43
Time (months)
45 36 41 26 33 24 24 14 15 6 3 0 0 0
Mok, ESMO 2012
CTONG 902
PFS and OS in patients with EGFR WT and ERCC1 IHC+ status (22 Jun 2012)
PFS
1.0 0.8
1.0 0.8

PFS according to IRC
Erlotinib (n=226) Placebo (n=225)
PFS probability
0.6 0.4 0.2 0 0 2
200 200 7.4 10.0
HR=0.58 (0.46–0.72)
Log-rank p<0.0001
4
177 179
No mutation detected KRAS (22%) EGFR (17%) EML4-ALK (7%) Double mutants (3%) BRAF (2%) AKT1
NRAS MEK1 MET AMP HER2 PIK3CA
Frequency of driver genes in subgroups of NSCLC in Chinese
NSCLC
FGER2 0.6%
DDR2 1% BRAF 2% PIK3CA 4% unknown 30% EGFR 28% PTEN 10%
c-MET 5%
KRAS 5%
STK11 8%
EML4-ALK 6%
An SJ, Wu YL. PLoS One June 2012
Frequency of driver genes in subgroups of NSCLC in Chinese
Screening Study treatment
Gemcitabine 1,250mg/m2 (d1, 8) + carboplatin AUC=5 or cisplatin 75mg/m2 (d1) + erlotinib 150mg/day (d15–28); q4wks x 6 cycles GC-erlotinib (n=226) R 1:1; stratified by stage, histology, smoking status and chemo regimen Gemcitabine 1,250mg/m2 (d1, 8) + carboplatin AUC=5 or cisplatin 75mg/m2 (d1) + placebo (d15–28); q4wks x 6 cycles GC-placebo (n=225)
Maintenance phase
Erlotinib 150mg/day
PD
Previously untreated stage IIIB/IV NSCLC, PS 0/1 (n=451)
Placebo
PD
Erlotinib 150mg/day Secondary endpoints: subgroup analyses, OS in all patients and subgroups, ORR, duration of response, TTP, NPR at 16 weeks, safety, QoL