br.21 study design *2:1 randomization r stratified by: centre ps, 0/1 vs 2/3 response to prior rx...

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