A Randomized Placebo Controlled Study of Erlotinib OSI774, Tarceva versus Placebo in Patients with I - PowerPoint PPT Presentation

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A Randomized Placebo Controlled Study of Erlotinib OSI774, Tarceva versus Placebo in Patients with I

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Histology. 0.0065. Gender. BR.21 Summary of Treatment Effect: Response. NOT Significant ... with Squamous Cell Histology. Response Rates by Ethnicity. 28/374. 8 ... – PowerPoint PPT presentation

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Title: A Randomized Placebo Controlled Study of Erlotinib OSI774, Tarceva versus Placebo in Patients with I


1
A Randomized Placebo Controlled Study of
Erlotinib (OSI-774, Tarceva?) versus Placebo in
Patients with Incurable Non-Small Cell Lung
Cancer Who Have Failed Standard Therapy for
Advanced or Metastatic DiseaseNational Cancer
Institute of Canada Trial BR.21 Clinical
Predictors of Response and Prognostic Markers of
Survival

FA Shepherd, MD FRCPC
Scott Taylor Chair in Lung Cancer
Research Princess Margaret Hospital, Professor
of Medicine, University of Toronto
2
BR.21 Study Design - 2
Stratified by Centre PS, 0/1 vs 2/3 Response to
prior Rx (CR/PRSDPD) Prior regimens, (1
vs 2) Prior platinum, (Yes vs no)
Erlotinib 150 mg daily
RANDOM I ZE
Placebo 150 mg daily
21Randomization
3
BR.21 Study Endpoints
  • Primary
  • Overall survival
  • Secondary
  • Time to deterioration of cough, dyspnea and pain
    (QoL, QLQC30 QLQCLC13)
  • Progression-free survival
  • Response rate duration of response
  • Toxicity tolerability

4
BR.21 Statistical Considerations
  • Median survival of untreated patients was
    estimated to be 4 months
  • Original HR 0.67
  • Revised HR 0.75 (before any analyses)
  • Goal detect an improvement in median survival of
    33
  • 90 power and a 2-sided 5 level test
  • 700 patients required to enter the study over 14
    months with 6 months follow-up 582 events
    required

5
BR.21 Results
  • 731 patients randomized Aug/01 Jan/03
  • 22 ineligible
  • gt2 regimens (9)
  • Only single agent in young patient (2)
  • CT or RT given within 2-4 weeks, concurrent CT
    (5)
  • Biochemical abnormalities (4)
  • Symptomatic CNS metastases (2)
  • Efficacy analyses
  • All 731 patients included
  • Only 7 (lt1) patients lost to follow-up
  • All treated patients (727) included in safety
    analyses

6
BR.21 Patient Characteristics
7
BR.21 Patient Characteristics
8
NCIC CTG BR.21 Best Response (N638)
9
BR.21 Summary of Treatment Effect Response
10
BR.21 Summary of Treatment Effect Response
NOT Significant EGFR Status (Trend)
PS
Prior platinum Prior response
Number of prior regimens
11
BR.21 Progression Free Survival
Months
Adjusted for stratification factors (except
centre) AND EGFR status
12
BR.21 Overall Survival
Adjusted for stratification factors (except
centre) AND EGFR status
Adjusted for stratification factors (except
centre) AND EGFR status
13
Secondary EndpointsMedian Time to Deterioration
and PFS (weeks)
14
EGFR GENE MUTATIONS
  • Predictive of response
  • More frequent in females
  • More frequent in adenocarcinoma
  • More frequent in non-smokers
  • More frequent in Asians
  • Does the absence of a mutation predict that a
    patient will not benefit from erlotinib???

15
DEFINITION OF BENEFIT
  • Response
  • Survival
  • Symptom improvement
  • Any permutation and combination of the above

16
Tumor Response (CRPR)Not a Good Surrogate for
Clinical Benefit with Erlotinib
17
BR.21 Summary of Treatment Effect Survival
significant predictor in the multivariate
analysis.
18
Tumor Response by Gender
19
Question Is there clinical benefit with
erlotinib in males? A. Yes
20
Survival for Females
21
Survival for Males
22
Tumor Response by Histology
23
Question Is there clinical benefit with
erltoinib in squamous cell carcinomas? A. Yes
24
Survival for Adenocarcinomas
25
Survival for Squamous Cell Ca.
26
Tumor Response by Smoking Status
27
Question Is there clinical benefit with
erlotinib in current/ex-smokers? A. Yes
28
Survival for Non-Smokers
29
Survival for Current/Ex-Smokers
30
Question Is the survival advantage lost for
patients who continue to smoke? A. Unclear
31
Current Smokers
32
Ex-Smokers
Note Incomplete information about when patients
stopped smoking
33
Question Is there a survival advantage for
male smokers with squamous cell carcinoma? A.
Yes
34
Current/Ex-Smoking Males with Squamous Cell
Histology
35
Response Rates by Ethnicity
36
Question Is there clinical benefit with
erlotinib in non-Orientals? A. Yes
37
Oriental Ethnicity
38
Non-Oriental Ethnicity
39
BR.21 Summary
  • This is the first placebo controlled randomized
    trial to confirm that an oral tyrosine kinase
    inhibitor of EGFR can prolong survival
  • Treatment with erlotinib was associated with
    significantly
  • longer overall survival
  • longer progression free survival
  • improved lung cancer-related symptoms
  • improved QoL

40
Tarceva - BR.21Summary of Subanalyses
  • Tumor response (CRPR) not a good surrogate for
    clinical benefit with erlotinib
  • Clinical benefit of erlotinib across subsets
  • Females and Males derived benefit
  • Benefit not just in adenocarcinomas
  • Benefit also in current- and ex-smokers
  • Orientals and non-Orientals derived benefit

41
Acknowledgements
  • Support
  • National Cancer Institute of Canada
  • OSIP, Drs. Clark and Santabarbara
  • Thank you to the NCIC CTG central office staff in
    Kingston, Ontario, Canada, and..

42
Thank you to all patients and investigators from
around the globe
Sweden
Germany
Romania
Greece
USA
Israel
Hong Kong
Mexico
Thailand
Singapore
Brazil
Australia
South Africa
Argentina
New Zealand
Chile
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