1. IDEAL 1 and IDEAL 2

2. BR.21 Study Design R Stratified by: Centre Erlotinib* 150mg/day
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
BR 21
Shepherd et al. N Engl J Med. 2005;353: 2

3. BR.21 Progression-Free Survival
___ Erlotinib, _____ Placebo
2.2 mos mos
*HR 0.61, p <0.0001
*Adjusted for stratification factors (except centre) AND EGFR status
BR 21
Months
Shepherd et al. N Engl J Med. 2005;353:

4. Survival time (months)
BR.21: Overall Survival
1.00
0.75
0.50
0.25
HR=0.70 (95% CI, ); P < 0.001*
*HR and P-value adjusted for stratification factors at randomization plus HER1/EGFR status.
Survival distribution function
31%
42.5% improvement in median survival
Pre-specified analyses in the statistical analysis plan for study BR.21 included stratifications on the basis of performance status, prior therapy (including platinum therapy), responsiveness to prior therapy, and HER1/EGFR status.
Treatment of NSCLC patients with erlotinib resulted in a statistically significant improvement in the primary endpoint of overall survival versus placebo.
In a univariate analysis of all patients, the hazard ratio was 0.72 (ie, patients treated with erlotinib had a 28% better chance of survival compared with placebo)
Patients treated with erlotinib (median survival=6.7 months) survived 30% longer than placebo-treated patients (median survival=4.7 months).
One-year survival rates were increased 48% by treatment with erlotinib.
Erlotinib is the only HER1/EGFR inhibitor proven to prolong the survival of patients with advanced, refractory NSCLC.
Erlotinib
Placebo
21%
Survival time (months)
Shepherd et al. N Engl J Med. 2005;353: 4 4

5. IPASS Study Design R Primary endpoint: PFS
Gefitinib 250mg/day
Chemonaïve advanced NSCLC
Adenocarcinoma
Non-smoker or light smoker
N = 1217 R
Paclitaxel (200 mg/m2, IV, d1) plus carboplatin (AUC=5 or 6 mg/min) repeated every 3 weeks up to 6 cycles
Primary endpoint: PFS
Secondary endpoints: ORR, OS, QoL and safety
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med Sep 3;361(10):
Mok TS, et al. N Engl J Med Sep 3;361(10): 5

6. IPASS: PFS and OS by Known EGFR Mutation Status
1.0
1.0
Gefitinib EGFR M+
Gefitinib EGFR M-
C / P EGFR M+
C / P EGFR M- 4 8 16 24 12 20
0.8
0.8
Mutation +
0.6
0.6
Probability of survival
0.4
0.4
Probability of progression-free survival
0.2
0.2
Mutation -
0.0
0.0 4 8 12 16 20 24 28 32 36
IPASS 40 44 48
Time from randomisation (months)
Time from randomisation (months) 52
Patients at risk excludes censored patients and those who have experienced an event
Yang CH et al. ESMO 2010 6 6 6

7. INTEREST Study Design Endpoints Patients IRESSA 250 mg/day
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
IRESSA
250 mg/day
1:1 randomization
Docetaxel
74 mg.m2 every 3 weeks
INTEREST was an international, multicenter, randomized, open-label, parallel-group, Phase III study of IRESSA (gefitinib) versus docetaxel in patients with locally advanced or metastatic recurrent NSCLC who were pre-treated with platinum-based chemotherapy.
Eligible patients were at least 18 years of age with NSCLC that had progressed or recurred following one or two prior therapies (at least one platinum based) and with a performance status of 0 to 2 and a life expectancy of >8 weeks.
Patients were randomized to receive either IRESSA (250 mg/day orally) or docetaxel (1-hour 75 mg/m2 infusion every 3 weeks).
The primary endpoint was overall survival using co-primary analyses of non-inferiority in all patients and superiority in patients with high epidermal growth factor receptor (EGFR) gene copy number.
Secondary endpoints compared progression-free survival, objective response rate, quality of life, disease-related symptoms and safety and tolerability for IRESSA and docetaxel.
Exploratory endpoints included the efficacy outcomes in biomarker subgroups defined by EGFR expression by immunohistochemistry (IHC), EGFR mutation and K-RAS mutation status.
aModified Hochberg procedure applied to control for multiple testing CT: chemotherapy; PS: performance status
Kim ES, et al. Lancet Nov 22;372(9652): 7 7

8. 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
0.8
HR (96% CI) = (0.905, 1.150)
HR (95% CI) = 1.09 (0.78, 1.51)
P =
0.6
Probability of survival
Gefitinib
Docetaxel
0.4
0.2
Pre-treated NSCLC INTEREST STUDY (D791GC00001)
INTEREST was a Phase III, randomized, open-label, parallel-group, international, multicentre trial comparing IRESSA to docetaxel in 1466 patients with locally advanced or metastatic NSCLC who had previously received platinum-based chemotherapy and were eligible for further chemotherapy. Pre-planned exploratory subgroup analysis of 44 EGFR mutation positive patients provides supportive evidence for the approved indication. For patients with EGFR mutations, IRESSA was superior to docetaxel in terms of PFS (HR 0.16, 95% CI 0.05 to 0.49, p=0.0012) and ORR (42.1% vs 21.1%, p= ).
Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet Nov 22;372(9652):
0.0 20 36 40 20 40
Months
Months
Kim ES, et al. Lancet Nov 22;372(9652): 8

9. SATURN Study Design R Erlotinib 150mg/day Placebo Run-in Period:
Patients with advanced NSCLC
Treatment with four cycles of platinum-doublet chemo
N = 1949
Erlotinib 150mg/day
Eligibility:
No progressive disease
N = 889 R
Placebo
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
Cappuzzo F, et al. Lancet Oncol Jun;11(6):521-9.

10. SATURN: Erlotinib vs. Placebo in NSCLC After Chemotherapy
PFS OS
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
Erlotinib (n=437)
Placebo (n=447)
Erlotinib (n=438)
Placebo (n=451)
HR=0.71 (0.62–0.82)
Log-rank p<0.0001
HR=0.81 (0.70–0.95)
Log-rank p=0.0088
Probability
Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, Esteban E, Molinier O, Brugger W, Melezínek I, Klingelschmitt G, Klughammer B, Giaccone G; SATURN investigators. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol Jun;11(6):521-9.
Time (weeks)
Time (weeks)
Cappuzzo F, et al. Lancet Oncol Jun;11(6):521-9. 10

11. SATURN: EGFR Activating Mutations
PFS1
OS2
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
HR=0.10 (0.04–0.25) Log-rank p<0.0001
HR=0.83 (0.34–2.02) Log-rank p=0.6810
Probability
Erlotinib (n=22)
Placebo (n=27)
Erlotinib (n=22)
Placebo (n=27)
Significantly improved PFS with erlotinib vs. placebo in patients with EGFR MUT +ve disease
OS data not yet mature (N.B. 67% of patients with EGFR MUT +ve disease in placebo arm received a second-line EGFR TKI)
Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, Esteban E, Molinier O, Brugger W, Melezínek I, Klingelschmitt G, Klughammer B, Giaccone G; SATURN investigators. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol Jun;11(6):521-9.
Brugger, et al. J Thorac Oncol 2009;4 (Suppl. 1):S348–9 (Abs. B9.1)
Time (weeks)
Time (months)
1. Cappuzzo F, et al. Lancet Oncol Jun;11(6):521-9.
2. Brugger, et al. J Thorac Oncol 2009;4 (Suppl. 1):S348–9 (Abs. B9.1) 11 11 11

12. PFS: Overall Population
Dacomitinib versus Erlotinib Phase ll
Overall population
100 90 80 70 60 50 40 30 20 10
PF (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)
Progression-free survival probability (%)
Dacomitinib Phase 2
Unstratified analysis: Hazard ratio = (95% CI: 0.490–0.945) Log-rank P-value = 0.019
Time (weeks)
CI = confidence interval
Post-baseline tumor assessments were initiated at week 8 and conducted every 4 weeks thereafter.
Boyer et al ASCO Abstract LBA7523.

13. 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
10-63
PF-8045
29-63 7
2-4
119
Afatinib
1. Oncogene 2008;27: Cancer Res 2006;66: Science 2004;304: JNCI 2005;97: Cancer Res 2007; 67:

14. PFS by independent review
Afatinib
Statistically significant across almost all subgroups