br.21 schema

BR.21 schema

Stratified by

Centre

PS (0/1 vs 2/3)

Response prior Rx (CR/PR:SD:PD)

Prior regimens (1 vs 2)

Prior platinum (Yes vs no)

TarcevaTM

150mg daily

Placebo‘150mg’ daily

RANDOM I SE*

PS = performance status; CR = complete response PR = partial response SD = stable disease; PD = progressive disease; *2:1 randomisation

Study endpoints

• Primary– overall survival

• Secondary– progression-free survival (PFS)– time to deterioration of cough, dyspnoea, pain

as per EORTC QLQ-C30 + QLQ-LC13– response rates, duration– toxicity and tolerability– tissue HER1/EGFR versus outcome and safety– TarcevaTM trough pharmacokinetics

HER/EGFR = epidermal growth factor receptor

Key eligibility criteria

• Confirmed NSCLC, Stage IIIB or IV• Age ³18 years • PS 0, 1, 2 or 3• Measurable or non-measurable disease• One or two prior chemotherapy regimens• Adequate organ function• HER1/EGFR+ not required• No prior HER1/EGFR inhibitors• No prior malignancies or uncontrolled CNS M1• Written informed consent

NSCLC = non-small-cell lung cancer; CNS M1 = symptomatic central nervous system metastasis

BR.21 patient characteristics

CharacteristicTarceva

TM

(n=488)

Placebo(n=243)

Median age (years) 62 59

Female (%) 35 34

PS 0, 1 (%) 13, 52 14, 54

PS 2, 3 (%) 26, 9 23, 9

Adenocarcinoma (%) 50 49

Prior regimens 1, 2, 3 (%) 50, 49, 1 50, 49, 1

Prior platinum (%) 93 92

Response to prior chemotherapy (%)

CR/PR 40 40

SD 39 39

PD 21 21

Measurable disease (%) 88 87

*HR and p-value adjusted for stratification factors at randomisation + HER1/EGFR status

Overall survival: all patients

42.5% improvement in median survival

Su

rviv

al d

istr

ibu

tio

n f

un

ctio

n

Survival time (months)

TarcevaTM

Placebo

HR* = 0.73, p<0.001

TarcevaTM (n=488)

Placebo (n=243)

Median survival (months) 6.7 4.7

1-year survival (%) 31 21

1.00

0.75

0.50

0.25

00 5 10 15 20 25 30

HR* = 0.73, p<0.001

Survival after eliminating CR/PRs

• The TarcevaTM benefit is still present after eliminating CRs and PRs

TarcevaTM Placebo

n Median n Median HR p-value

SD/PD/NE 449 5.7 241 4.7 0.86 0.073

SD/PD 367 7.4 204 6.7 0.82 0.037

• Exploratory analyses in BR.21 dataset

Ramalingam, S. et al. Oncologist 2006;11:655-665

Efficacy data for docetaxel, pemetrexed & erlotinib

BR.21: summary of significant clinical predictors of response

ErlotinibPatients (%)

(n=427) p*

Gender Female (146) 14.4 0.006

Male (281) 6.1

Histology Adenocarcinoma (209) 13.9<0.001

Other (218) 4.1

Ethnicity Asian (53) 18.90.02

Other (374) 7.5

Ever smoked Yes (311) 3.8

<0.001No (93) 24.7

Unknown (23) 13.0

*Significance between subgroups

BR.21: Survival Across Subgroups

HR = hash mark on horizontal bar.95% CI = length of horizontal bar.

TARCEVA™ (erlotinib) PI.

Tarceva: Placebo

PS 0-1PS 2-3

MaleFemale

<65 y65 y

AdenocarcinomaSquamous cell carcinomaOther histology

Prior weight loss <5%Prior wt loss 5%-10%Prior wt loss >10%

Never smokedCurrent/ex-smoker

1 prior regimen2 prior regimens

Subset n

731

486245

475256

452279

365222144

48613281

146545

364367

0 1.0 2.0 2.5

Decreasedrisk of death

Increasedrisk of death

1.50.5

BR.21: Survival Across Subgroups Cont’d

0 1.0 2.0 2.5

Decreasedrisk of death

Increasedrisk of death

Tarceva: Placebo

Prior platinumNo prior platinumPrior taxaneNo prior taxaneBest prior response: CR/PRBest prior response: SDBest prior response: PD<6 mo since diagnosis6-12 mo since diagnosis>12 mo since diagnosisEGFR-positiveEGFR-negativeEGFR unmeasuredCaucasianAsian

Stage IV at diagnosisStage <IV at diagnosis

Subset n

1.50.5

67853

26746429228715297

24239212711149356791

329402

731

HR = hash mark on horizontal bar.95% CI = length of horizontal bar.

TARCEVA™ (erlotinib) PI.

Clinical Benefit of Erlotinib inMale Smokers with SCC

Clark, Abstract #7166, Poster

NCIC CTG BR.21 : Survival for Male, Ever Smokers with SCC

Clark GM et al. ASCO 2006, Abs #7166.

BR.21 Symptom Benefit

Median time to deterioration (weeks)†

Parameter TarcevaTM

PlaceboAdjusted*

p-value

Cough 28.14 15.71 0.041

Dyspnoea 20.43 12.14 0.031

Pain 12.14 8.14 0.040

*Adjustment for multiple testing

†Patients were considered to have deteriorated symptoms if the change in

score from baseline for each symptom was 10 points or higher at any time-point after baseline assessment

QoL outcomes for second-line therapy

Agent Tool QoL outcomes Symptom outcomes

Tarceva1 EORTC:

QLQ-C30

QLQ-LC13

Significant improvement in global, physical, and emotional QoL versus BSC

Significant increase in time to deterioration of symptoms (cough, dyspnoea, pain) versus BSC

Docetaxel2 Lung Cancer

Symptom Scale (LCSS)

– No significant improvement for docetaxel 75mg/m2 compared with BSC

Pemetrexed3 LCSS – No significant

difference compared with docetaxel 75mg/m2

1 Bezjak A, et al. J Clin Oncol 2006;24:3831–7; 2 Dancey J, et al. Lung Cancer 2004;43:183–94; 3 Hanna N, et al. J Clin Oncol 2004;22:1589–97

BR.21 adverse events (%)

TarcevaTM

(n=485)

Placebo(n=242)

Any Grade 3, 4 Any Grade 3, 4

Rash 75 9 17 0

Diarrhoea 54 6 18 <1

Nausea 33 3 24 2

Vomiting 23 2 19 2

Stomatitis 17 <1 3 0

Fatigue 52 18 45 20

Ocular (all) 27 1 9 <1

Anorexia 52 9 38 5

Infection 24 4 15 2

Comparison of phase III trials in relapsed NSCLC: haematological toxicity

Adverse event (grade 3/4)

Tarceva (150mg/day)

Docetaxel (75mg/m

2)

Pemetrexed (500mg/m

2)

Neutropenia 1 40.2 5.3

Febrile neutropenia 1 12.7 1.9

Anaemia 1 4.3 4.2

Thrombocytopenia 1 0.4 1.9

Patients (%)

Shepherd F, et al. N Engl J Med 2005;353:123–32 Hanna N, et al. J Clin Oncol 2004;22:1589–97

ASCO 2006 Abstracts

1st-line Erlotinib in Elderly Patientswith Advanced NSCLCJackman, Abstract #7168

Study DesignNon-randomized, open label, Phase II trial

Key inclusion criteria

Endpoints Treatment

• Age > 70 years

• Stage IIIb/IV

• ECOG PS 0 – 2

• >3 wks since RT or major surgery

• Primary: survival

• Secondary include RR, TTP, toxicity, QoL, symptom response

• Erlotinib 150 mg/day until PD or unacceptable toxicity

• Dose reductions (100 mg; 50 mg) permitted for AE’s

Jackman DM et al. ASCO 2006, Abs #7168.

0.0

0.25

0.50

0.75

1.0

0 26 52 78 104

Median Survival 41 weeks52-week survival 40.4%


Survival

Jackman DM et al. ASCO 2006, Abs #7168.Jackman DM et al. 11th WCLC 2005, Abstract #O-188.


Poster

Symptom Response

0%

20%

40%

60%

80%

100%

Dyspnea Cough Fatigue Pain Loss ofappetite

Improved Stable Worse

(n=47) (n=45) (n=50) (n=22)(n=37)

15

15

70

11

24

64

20

22

58

18

9

73

15

15

70


Results• For the 64 patients eligible for QoL analysis, there was no

statistically significant improvement in overall LCSS score.• Patients who achieved PR or SD had statistically significant

improvements in their overall score QoL as measured by LCSS.

Conclusions • Patients over the age of 70 years had a median survival of 10.9

months when treated with erlotinib in the first-line.• Erlotinib in this population was also associated with improvements in

key symptoms of dyspnea, cough, fatigue, pain and loss of appetite.• Improvements in overall LCSS score were noted in patients who

achieved disease control (PR or SD).

Jackman DM et al. ASCO 2006, Abs #7168.

1st-line Erlotinib in Advanced NSCLCwith Good PrognosisAkerley, Abstract #7178

Study Design Stage IIIb or IV NSCLC

No prior chemotherapy formetastatic disease

Good prognosis defined as:

• No brain metastases

• <10% weight loss

• O2 use not due to malignancy

• PS 0 or 1• No immediate need for

chemotherapy

Erlotinib

150 mg/day

Objective or symptomatic progression

Switch to chemotherapy

Primary Objective

Achieve 6-month chemotherapy-progression-free survival rate that is significantly higher than the historically observed 31%

Akerley W et al. ASCO 2006, Abs #7178.


Response

Subsequent Chemotherapyand Outcomes n (%)

Too early to assess 5 (14)

Never received chemo 11 (31)

PR 9 (26)

SD 11 (31)

PD 4 (11)

Response to Erlotinib n (%)

PR 6 (15)

SD 11 (28)

PD 23 (58)

Rash Correlates with Duration of Therapy

Grade of Rash Median duration of Tx

0 – 1 7.8 weeks

3 – 4 17.7 weeks

Progression-free Survival*

6-month PFS 56%

*Chemotherapy-progression-free survival: time from study entry to progression on

chemotherapy or erlotinib if patient refused chemotherapy.



Overall Survival


1st-line Erlotinib in Elderly Patientswith Advanced NSCLCAkerley, Abstract #7178

Conclusions • The overall response rate was 15%; the 6-month PFS rate is

56%.

• Rash predicts the duration of erlotinib effectiveness.

• Never smokers show a better survival outcome than ever smokers.

• Survival and PFS in this population of minimally selected patients appear comparable to that with chemotherapy.

• A randomized trial is warranted to further investigate the results of this trial.


br.21 schema

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