Post on 31-Dec-2015
description
BR.21 Study Design
*2:1 RandomizationR
Stratified by:CentrePS, 0/1 vs 2/3Response to prior Rx (CR/PR:SD:PD)Prior regimens, (1 vs 2)Prior platinum, (Yes vs no)
Placebo “150 mg” daily
Erlotinib* 150mg/day
Shepherd et al. N Engl J Med. 2005;353:123-132.
BR.21 Progression-Free Survival
*Adjusted for stratification factors (except centre) AND EGFR status
SUMMARY STATISTICS:Log-Rank test for equality of groups: p=0.0000Wilcoxon test for equality of groups: p=0.0000Survival rate at 12 months for OSI-774: 8% - % C.I. ( 5%, 10%)Survival rate at 12 months for Placebo: 2% - % C.I. ( 0%, 4%)Hazard Ratio of Placebo/OSI-774: 1.572 - 95 % C.I. (1.337, 1.848)
OSI-774 Placebo
Perc
enta
ge
0
20
40
60
80
100
Time (months) # At Risk(OSI-774) # At Risk(Placebo)
0.0488243
5.015334
10.0526
15.081
20.010Months
___ Erlotinib, _____ Placebo
2.2 mos 1.8 mos
*HR 0.61, p <0.0001
Shepherd et al. N Engl J Med. 2005;353:123-132.
21%
31%
*HR and P-value adjusted for stratification factors at randomization plus HER1/EGFR status.
BR.21: Overall Survival
42.5% improvement in median survival
Survival time (months)
Erlotinib
Placebo
HR=0.70 (95% CI, 0.58-0.85); P < 0.001*
1.00
0.75
0.50
0.25
00 5 10 15 20 25 30
Surv
ival
dis
trib
ution
func
tion
Shepherd et al. N Engl J Med. 2005;353:123-132.
IPASS Study Design
• Primary endpoint: PFS
• Secondary endpoints: ORR, OS, QoL and safety
Gefitinib 250mg/dayChemonaïve advanced NSCLC Adenocarcinoma Non-smoker or light smoker N = 1217 Paclitaxel (200 mg/m2, IV, d1)
plus carboplatin (AUC=5 or 6 mg/min) repeated every 3
weeks up to 6 cycles
R
Mok TS, et al. N Engl J Med. 2009 Sep 3;361(10):947-57.
IPASS: PFS and OS by Known EGFR Mutation StatusP
rob
abil
ity
of
pro
gre
ssio
n-f
ree
surv
ival
52
4 8 16 2412 20
Time from randomisation (months)
1.0
0.8
0.6
0.4
0.2
0.00
PFS (2008)Gefitinib EGFR M+Gefitinib EGFR M-C / P EGFR M+C / P EGFR M-
1.0
0.8
0.6
0.4
0.2
0.00 4 8 12 16 20 44
Time from randomisation (months)P
rob
abil
ity
of
surv
ival
OS (2010)
24 28 32 36 40 48
Mutation +
Mutation -
Patients at risk excludes censored patients and those who have experienced an event
Yang CH et al. ESMO 2010
INTEREST Study Design
aModified Hochberg procedure applied to control for multiple testingCT: chemotherapy; PS: performance status
Patients• Age ≥18 years
• Life expectancy≥8 weeks
• Progressive or recurrent disease following CT
• Considered candidates for further CT with docetaxel
• 1 or 2 CT regimens(≥1 platinum)
• PS 0-2
Primary• Overall survival(co-primary analysesa of non-inferiority in all patients and superiority in patients with high EGFR gene copy number)
Secondary• Progression-free survival• Objective response rate• Quality of life• Disease-related symptoms• Safety and tolerability
Exploratory• Biomarkers
Endpoints
IRESSA250 mg/day
IRESSA250 mg/day
Docetaxel74 mg.m2
every 3 weeks
Docetaxel74 mg.m2
every 3 weeks
1:1 randomization
Kim ES, et al. Lancet. 2008 Nov 22;372(9652):1809-18.
INTEREST: Gefitinib vs. Docetaxel in NSCLC After Chemotherapy
OS in overall study population
Gefitinib demonstrated non-inferior survival compared with docetaxel
Kim ES, et al. Lancet. 2008 Nov 22;372(9652):1809-18.
0 36 40
0.0
0.2
0.4
0.6
0.8
1.0
Months
Prob
abili
ty o
f sur
viva
l HR (96% CI) = 1.020 (0.905, 1.150)
OS in patients with high EGFR gene copy number
20
GefitinibDocetaxel
0 40Months
20
HR (95% CI) = 1.09 (0.78, 1.51)P = 0.6199
SATURN Study Design
• Primary endpoint: PFS in all patients; PFS in patients with EGFR IHC-positive tumours
• Secondary endpoints: OS in ITT and EGFR-positive tumours, PFS in EGFR-negative tumours, time to progression, tumour response, QoL
Erlotinib 150mg/dayRun-in Period:• Patients with
advanced NSCLC• Treatment with
four cycles of platinum-doublet chemo
• N = 1949Placebo
REligibility:• No progressive
disease• N = 889
Cappuzzo F, et al. Lancet Oncol. 2010 Jun;11(6):521-9.
SATURN: Erlotinib vs. Placebo in NSCLC After Chemotherapy
Pro
bab
ilit
y
Time (weeks)
PFS OS
0 8 16 24 32 40 48 56 64 72 80 88 96
Time (weeks)
0 8 16 24 32 40 48 56 64 72 80 88 96
Erlotinib (n=438)
Placebo (n=451)
Erlotinib (n=437)
Placebo (n=447)
HR=0.71 (0.62–0.82)Log-rank p<0.0001
HR=0.81 (0.70–0.95)Log-rank p=0.0088
1.0
0.8
0.6
0.4
0.2
0
1.0
0.8
0.6
0.4
0.2
0
Cappuzzo F, et al. Lancet Oncol. 2010 Jun;11(6):521-9.
SATURN: EGFR Activating Mutations
Time (weeks)
0 8 16 24 32 40 48 56 64 72 80 88 96
Pro
bab
ilit
y
HR=0.10 (0.04–0.25)Log-rank p<0.0001
1.0
0.8
0.6
0.4
0.2
0
PFS1
Erlotinib (n=22)
Placebo (n=27)
1.0
0.8
0.6
0.4
0.2
0
Time (months)
HR=0.83 (0.34–2.02)Log-rank p=0.6810
Erlotinib (n=22)
Placebo (n=27)
OS2
0 3 6 9 12 15 18 21 24 27 30 33 36
1. Cappuzzo F, et al. Lancet Oncol. 2010 Jun;11(6):521-9.
2. Brugger, et al. J Thorac Oncol 2009;4 (Suppl. 1):S348–9 (Abs. B9.1)
PFS: Overall PopulationPFS: Overall Population Overall population
100908070605040302010
0
Pro
gre
ssio
n-f
ree
surv
ival
pro
bab
ilit
y (%
)
0 5 10 15 20 25 30 35 40 45 50 55 60
Time (weeks)
Unstratified analysis:Hazard ratio = 0.681(95% CI: 0.490–0.945)Log-rank P-value = 0.019
PF299804 (n=94)Median: 12.4 weeks(95% CI: 8.3–16.1)
Erlotinib (n=94)Median: 8.3 weeks(95% CI: 8.0–11.4)
CI = confidence intervalPost-baseline tumor assessments were initiated at week 8 and conducted every 4 weeks thereafter.
Boyer et al ASCO 2010. Abstract LBA7523.
Dacomitinib versus Erlotinib Phase ll
AFATINIB: PRECLINICAL ACTIVITYDrug IC50 (nM)
WT L858R Exon 19 Del L858R/T790M
Afatinib1 60 0.7 0.5 50
Erlotinib2 110 40 3.8 >4,000
Gefitinib3, 4 157 50 10-63 >4,000
PF-8045 29-63 7 2-4 119
1. Oncogene 2008;27:4702-4711. 2.Cancer Res 2006;66:8163-71. 3. Science 2004;304:1497. 4. JNCI 2005;97:1185-94. 5. Cancer Res 2007; 67:11924-32.
PFS by independent review
Statistically significant across almost all subgroups