非小细胞肺癌表皮生长因子受体酪氨酸激酶抑制剂(英文)

18
12
Months YMC
J Chemother 2005;17:679
Survival according to response or not
Fig. 1 100 90 80
Complete or partial response (n=12) median 20.1M
Stable or progressive disease (n=24) median 4.7M
Primary endpoints
Objective tumour response
Symptom improvement (IDEAL 2) Gefitinib 500 mg/day
Safety (IDEAL 1)
Continue gefitinib until disease progression or unacceptable toxicity
YMC 7
Lancet 2005;366:1527-37
ISEL - Overall Survival
1.0
Median (months) Gefitinib 5.6 27% placebo 5.1 21%
0.8
Percent surviving
1 yr survival
0.6 0.4 0.2 0.0
YMC
ISEL Survival: Orientals
1.0
Analysis Method HR and 95% CI
0.70 (0.49, 0.99) 0.65 (0.47, 0.91) 0.66 (0.48, 0.91)
p-value
0.046 0.012 0.010
0.8
Percent surviving
E N D
Gefitinib (250 mg) + *BSC
Primary endpoint:
SURVIVAL Secondary: TTF, OR QoL, safety
Randomisation
2:1 ratio
Placebo + *BSC
B E N E F I T
1692 patients in 210 centres across 28 countries 342 patients of oriental origin No Japanese/US sites *BSC= Best Supportive Care 2019/1/21
HR=0.89 (0.77, 1.02), p=0.0871 Stratified log rank test N=1692, deaths=976 Cox analysis, p=0.0299
——
IRESSA
------
Placebo
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16
2
8* 29*
YMC 5
FACT-L
*Time of 1st assessment
2019/1/21
IDEAL 1 and 2: overall survival by symptom improvement (250 mg/day)
Probability 1.0 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 Months from randomisation Patients Deaths Median (n) (months) (n) Improvement 27 18 13.3 No improvement 40 30 3.5
2019/1/21 YMC
IDEAL 1
Probability 1.0 0.8 0.6 0.4 0.2 0.0
IDEAL 2
0 2 4 6 8 10 12 14 16 18 20 Months from randomisation Patients (n) 44 58 Deaths (n) 26 56 Median (months) 13.6 3.7
70
60
15.4月
50
40 30 20 10 0 0
2019/1/21
3
6
9
12
YMC
15
18
21
13
Months
J Chemother 2005;17:679
Study Design of BR.21
Stratified by:
Centre PS (0/1 vs 2/3) Response to prior treatment (CR/PR:SD:PD) Prior regimens (1 vs 2) Prior platinum (yes vs no)
Other (218)
Asian (53) Other (374) Yes (311)
4.1
18.9 7.5 3.8
No (93)
Unknown (23)
24.7
13.0
<0.001
*Significance between subgroups **Data collected retrospectively In multiple logistic-regression analyses, only never having smoked (p<0.001) and adenocarcinoma histology (p=0.01) were associated with response 2019/1/21 YMC 15 Shepherd et al. NEJM 2005;353:123
Tarceva (n=488)
6.7 31
Placebo (n=243)
4.7 21
2019/1/21
Time (months)
YMC
2019/1/21
YMC
10
J Chemother 2005;17:679
RESULTS
• 3 CR, 9 PR, with a R.R. of 33.3%
• SD 14, control rate of 72.2%
All treatment-related toxicities were few and mild in severity, except one patient suffered from reversible grade 3 interstitial pneumonitis
2019/1/21
YMC
11
J Chemother 2005;17:679
Median survival: 9.5 months One-year survival rate: 45.1%
100 90 80 70 60 50 40 30 20 10 0 0
2019/1/21
2
4
6
8
10
12
14
16
PS = performance status 2019/1/21
R A N 2 D O M I S 1 E
YMC
Tarceva 150mg daily
Placebo
N Engl J Med 2005;353:123 –32 14
BR.21: Significant clinical predictors of response to Tarceva
Epidermal growth factor receptortyrosine kinase inhibitor in nonsmall-cell lung cancer
Yuh-Min Chen, MD, PhD. Chest Dept., Taipei VGH
2019/1/21 YMC 1
Activation of the epidermal growth factor receptor tyrosine kinase (EGFR-TK): a pivotal driver of carcinogenesis
IDEAL, IressaTM Dose Evaluation in Advanced Lung cancer
2019/1/21 YMC 4
Median time to improvement symptoms and QOL
Symptom/QOL measure
LCS
Median time to improvement, days
8
At risk: Gefitinib 1129 1023 901 761 588 455 325 245 175 113 76 45 19 9 Placebo 563 517 446 382 289 220 160 115 77 44 28 20 12 4
2019/1/21
Time (months)
6
Douillard et al 2002; Lynch et al 2003
ISEL (IRESSA Survival Evaluation in Lung Cancer): Clinical Trial Design
A double blind Phase III survival study comparing IRESSA (250mg) plus BSC vs. placebo plus BSC in patients with advanced NSCLC who have received 1–2 prior chemotherapy regimens and are refractory or intolerant to their most recent regimen
Ligand EGFR
EGFR-TK
PI3-K
pY pY pY
GRB2
SOS RAS RAF
STAT3 PTEN AKT
MEK
Gene transcription Cell-cycle progression
PP
MAPK
Proliferation/ maturation
DNA
Myc JunFos Myc
Tarceva treated pts (n) Gender Histology Ethnicity Ever smoked** Female (146) Male (281) Adenocarcinoma (209) R.R. (%) 14.4 6.1 13.9 p value*
0.006
<0.001 0.02
Cyclin D1 Cyclin D1
Survival (anti-apoptosis)
2019/1/21
Chemotherapy/ Metastasis radiotherapy Angiogenesis resistance YMC 2 Balaban et al 1996; Akimoto et al 1999; Wells 1999; Woodburn 1999;
Fra Baidu bibliotek
Hanahan 2000; Raymond et al 2000
TGFa
Monoclonal Antibodies
R R
Extracellula r Membrane
Intracellular
p
EGFR Tyrosine Kinase Inhibitors
p
Substrate
K K
p
p
p
p
Substrate
Stratified log rank Log rank Cox regression
0.6 0.4 0.2
—— IRESSA Placebo
5.5 M
9.5 M
0.0
------
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16
25 12 7 3 8 1 1
9
At risk: Gefitinib 235 221 199 179 145 119 95 78 64 51 40 Placebo 107 97 84 74 56 43 35 29 22 13 8
Improvement in Survival with Tarceva
1.00
42.5% improvement in median survival
Survival distribution function 0.75 Median survival (months) 1-year survival (%) 0.50
p
Proliferation Inhibit Apoptosis Angiogenesis
2019/1/21 Metastasis
Nucleus
YMC
Signalling Molecules
3
IDEAL 1 and 2 trial design
Randomisation
IDEAL 1 (n=209) 1 or 2 prior regimens IDEAL 2 (n=216) >2 prior regimens Gefitinib 250 mg/day