br.21 study design
DESCRIPTION
BR.21 Study Design. Stratified by: Centre PS, 0/1 vs 2/3 Response to prior Rx (CR/PR:SD:PD) Prior regimens, (1 vs 2) Prior platinum, (Yes vs no). Erlotinib * 150mg/day. R. * 2:1 Randomization. Placebo “150 mg” daily. - PowerPoint PPT PresentationTRANSCRIPT
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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.
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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.
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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.
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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.
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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
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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.
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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
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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.
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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.
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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)
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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
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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.
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PFS by independent review
Statistically significant across almost all subgroups