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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.

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br 21 study design
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
BR.21 Progression-Free Survival

___ Erlotinib, _____ Placebo

2.2 mos 1.8 mos

*HR 0.61, p <0.0001

*Adjusted for stratification factors (except centre) AND EGFR status

Months

Shepherd et al. N Engl J Med. 2005;353:123-132.

br 21 overall survival
BR.21: Overall Survival

1.00

0.75

0.50

0.25

0

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.

Survival distribution function

31%

42.5% improvement in median survival

Erlotinib

Placebo

21%

0 5 10 15 20 25 30

Survival time (months)

Shepherd et al. N Engl J Med. 2005;353:123-132.

ipass study design
IPASS Study Design

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, et al. N Engl J Med. 2009 Sep 3;361(10):947-57.

ipass pfs and os by known egfr mutation status
IPASS: PFS and OS by Known EGFR Mutation Status

Gefitinib EGFR M+

Gefitinib EGFR M-

C / P EGFR M+

C / P EGFR M-

4

8

12

16

20

24

PFS (2008)

OS (2010)

1.0

1.0

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

0

4

8

12

16

20

24

28

32

36

44

48

0

40

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

interest study design
INTEREST Study Design

Endpoints

  • 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

IRESSA

250 mg/day

1:1 randomization

Docetaxel

74 mg.m2 every 3 weeks

aModified Hochberg procedure applied to control for multiple testingCT: chemotherapy; PS: performance status

Kim ES, et al. Lancet. 2008 Nov 22;372(9652):1809-18.

interest gefitinib vs docetaxel in nsclc after chemotherapy
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) = 1.020 (0.905, 1.150)

HR (95% CI) = 1.09 (0.78, 1.51)

P = 0.6199

0.6

Probability of survival

Gefitinib

Docetaxel

0.4

0.2

0.0

20

36

40

20

40

0

0

Months

Months

Kim ES, et al. Lancet. 2008 Nov 22;372(9652):1809-18.

saturn study design
SATURN Study Design
  • 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. 2010 Jun;11(6):521-9.

saturn erlotinib vs placebo in nsclc after chemotherapy
SATURN: Erlotinib vs. Placebo in NSCLC After Chemotherapy

OS

PFS

1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

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

0 8 16 24 32 40 48 56 64 72 80 88 96

0 8 16 24 32 40 48 56 64 72 80 88 96

Time (weeks)

Time (weeks)

Cappuzzo F, et al. Lancet Oncol. 2010 Jun;11(6):521-9.

saturn egfr activating mutations
SATURN: EGFR Activating Mutations

PFS1

OS2

1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

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

0 3 6 9 12 15 18 21 24 27 30 33 36

0 8 16 24 32 40 48 56 64 72 80 88 96

Time (months)

Time (weeks)

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 population
PFS: Overall Population

Dacomitinib versus Erlotinib Phasell

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)

Progression-freesurvival probability (%)

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 50 55 60

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.

afatinib preclinical activity
AFATINIB: PRECLINICAL ACTIVITY

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
PFS by independent review

Statistically significant across almost all subgroups

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