肺癌驱动基因研究总结

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
Gene
CDKN2A PI3KCA PTEN FGFR1 EGFR
Event Type
Deletion/Mutation/Methylation Mutation Mutation/Deletion Amplification Amplification
Frequency
72% 16% 15% 15% 9%
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
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.
CTONG 902
PFS and OS in EGFR Mut+ subgroup (22 Jun 2012)
PFS
1.0 0.8
Erlotinib (n=49) Placebo (n=48) HR=0.25 (0.16–0.39) p<0.0001
OS
1.0 0.8
Erlotinib (n=49) Placebo (n=48) HR=0.48 (0.27–0.84) p=0.0092
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
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
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
EGFR
EGFR mutant 1st line trials : PFS and OS
PFS
EGFR TKI组 Gefitinib trials IPASS*1 (n= 261) 9.5 6.3 0.48 p<0.001 21.6 21.9 1.00(0.76-1.33) 化疗组 HR EGFR TKI组
非小细胞肺癌驱动基因研究
吴一龙 广东省肺癌研究所 广东省人民医院 广东省医学科学院
Treatment selection is moving from histologybased to targeting oncogenic drivers
1999 Histology-driven selection 2010 Targeting oncogenic drivers* Evolution of NSCLC treatment
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.
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)
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.
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
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：
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)
OS probability
0.6
0.4 0.2 0 0 4 9.5 8 12 18.4 16 20 24 28 32
Time (months)
E P 20 17 13 8 7 2 3 0 2 0 2 0 1 0 0 0 E P 20 17 16 13 15 9
Time (months)
15 6 13 3 8 1 6 0 3 0 0 0
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
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
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
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
E P
15.2
18.3
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 Time (months)
68 52 39 23 53 37 24 13 9 6 6 4 1 0 0 0
226 219 202 191 176 165 154 138 129 114 98 85 225 218 206 185 168 156 138 120 103 92 78 68
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
Mok, ESMO 2012
OS in ITT population (22 Jun 2012)
1.0 0.ห้องสมุดไป่ตู้ 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
Non-squamous Adenocarcinoma
Squamous
EGFR Mu Squamous-cell carcinoma
EGFR WT
Squamous
2008
KRAS
EGFR BRAF
PIK3CA ALK MET Unknown EGFR ALK+ Mu KRAS Mu Other nonToday squamous Squamous WT