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
Shepherd et al. N Engl J Med. 2005;353:123-132.
BR.21 Progression-Free Survival
100
___ Erlotinib, _____ Placebo
Percen tage
80
2.2 mos
60
1.8 mos
*HR 0.61, p <0.0001
40
*Adjusted for stratification factors (except centre) AND EGFR status
20
0
0.0
488
243
5.0
153
34 Months
10.0
15.0
20.0
52
6
8
1
1
0
Time (months)
# At Risk(OSI-774)
# At Risk(Placebo)
OSI-774
Placebo
SUMMARY STATISTICS:
Log-Rank tes t for equality of groups : p=0.0000
Wilc ox on tes t for equality of groups : p=0.0000
Shepherd et al. N Engl J Med. 2005;353:123-132.
BR.21: Overall Survival
Survival distribution function
1.00
0.75
Erlotinib
Placebo
(n=488)
(n=243)
Median survival (months)
6.7
4.7
1-year survival (%)
31
21
HR=0.70 (95% CI, 0.58-0.85); P < 0.001*
*HR and P-value adjusted for stratification factors at
randomization plus HER1/EGFR status.
0.50
31%
42.5% improvement in median survival
0.25
Erlotinib
21%
Placebo
0
0
5
10
15
20
25
30
Survival time (months)
Shepherd et al. N Engl J Med. 2005;353:123-132.
IPASS Study Design
Chemonaïve advanced NSCLC
Gefitinib 250mg/day
 Adenocarcinoma
 Non-smoker or light smoker
 N = 1217
• Primary endpoint: PFS
R
Paclitaxel (200 mg/m2, IV, d1)
plus carboplatin (AUC=5 or 6
mg/min) repeated every 3
weeks up to 6 cycles
• Secondary endpoints: ORR, OS, QoL and safety
Mok TS, et al. N Engl J Med. 2009 Sep 3;361(10):947-57.
1.0
Gefitinib EGFR M+
Gefitinib EGFR MC / P EGFR M+
C / P EGFR M-
0.8
0.6
0.4
0.2
0.0
1.0
Probability of survival
Probability of progression-free survival
IPASS: PFS
PFS and
(2008)OS by Known EGFR Mutation
OS (2010) Status
0.8
Mutation +
0.6
0.4
0.2
Mutation -
0.0
0 4
8 12 16 20 24
Time from randomisation (months)
0
4 8 12 16 20 24 28 32 36 40 44 48
Time from randomisation (months)
52
Patients at risk excludes censored patients and those who have experienced an event
Yang CH et al. ESMO 2010
INTEREST Study Design
Endpoints
Patients
• Age
≥18 years
• Life
expectancy
≥8 weeks
• Progressive
or recurrent
disease following CT
Primary
IRESSA
250 mg/day
1:1 randomization
• Considered
candidates
for further CT with
docetaxel
•1
or 2 CT regimens
(≥1 platinum)
• PS
Docetaxel
74 mg.m2
every 3 weeks
0-2
• Overall survival
(co-primary analysesa of noninferiority 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
aModified
Hochberg procedure applied to control for multiple testing
CT: chemotherapy; PS: performance status
Kim ES, et al. Lancet. 2008 Nov 22;372(9652):1809-18.
INTEREST: Gefitinib vs. Docetaxel in
NSCLC After Chemotherapy
Gefitinib demonstrated non-inferior survival compared with docetaxel
OS in overall study population
OS in patients with high EGFR gene
copy number
1.0
Probability of survival
0.8
HR (96% CI) = 1.020 (0.905, 1.150)
HR (95% CI) = 1.09 (0.78, 1.51)
P = 0.6199
0.6
Gefitinib
Docetaxel
0.4
0.2
0.0
0
20
Months
36
40 0
20
Months
40
Kim ES, et al. Lancet. 2008 Nov 22;372(9652):1809-18.
SATURN Study Design
Run-in Period:
•
Patients with
advanced NSCLC
•
Treatment with
four cycles of
platinumdoublet chemo
•
Erlotinib 150mg/day
Eligibility:
•
No progressive
disease
•
N = 889
R
Placebo
N = 1949
•
Primary endpoint: PFS in all patients; PFS in patients with EGFR IHCpositive tumours
•
Secondary endpoints: OS in ITT and EGFR-positive tumours, PFS in
EGFR-negative tumours, time to progression, tumour response, QoL
Cappuzzo F, et al. Lancet Oncol. 2010 Jun;11(6):521-9.
SATURN: Erlotinib vs. Placebo in
NSCLC After Chemotherapy
OS
PFS
1.0
1.0
Erlotinib (n=437)
Placebo (n=447)
HR=0.71 (0.62–0.82)
Log-rank p<0.0001
Probability
0.8
Erlotinib (n=438)
0.6
0.6
0.4
0.4
0.2
0.2
0
0
0
8 16 24 32 40 48 56 64 72 80 88 96
Time (weeks)
Placebo (n=451)
HR=0.81 (0.70–0.95)
Log-rank p=0.0088
0.8
0
8 16 24 32 40 48 56 64 72 80 88 96
Time (weeks)
Cappuzzo F, et al. Lancet Oncol. 2010 Jun;11(6):521-9.
SATURN: EGFR Activating
Mutations
1.0
Probability
0.8
PFS1
HR=0.10 (0.04–0.25)
Log-rank p<0.0001
0.6
0.4
0.4
0
Erlotinib (n=22)
Placebo (n=27)
0 8 16 24 32 40 48 56 64 72 80 88 96
Time (weeks)
HR=0.83 (0.34–2.02)
Log-rank p=0.6810
0.8
0.6
0.2
OS2
1.0
0.2
Erlotinib (n=22)
Placebo (n=27)
0
0
3 6 9 12 15 18 21 24 27 30 33 36
Time (months)
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.
Dacomitinib versus Erlotinib Phase ll
PFS: Overall Population
Progression-free
survival probability (%)
Overall population
100
90
80
70
60
50
40
30
20
10
0
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)
Unstratified analysis:
Hazard ratio = 0.681
(95% CI: 0.490–0.945)
Log-rank P-value = 0.019
0
5
10
15
20
25
30
35
40
45
Time (weeks)
CI = confidence interval
Post-baseline tumor assessments were initiated at week 8 and conducted every 4 weeks thereafter.
Boyer et al ASCO 2010. Abstract LBA7523.
50
55
60
AFATINIB: PRECLINICAL ACTIVITY
Drug
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