Title: A Randomized Placebo Controlled Study of Erlotinib OSI774, Tarceva versus Placebo in Patients with I
1A 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
2BR.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
3BR.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
4BR.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
5BR.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
6BR.21 Patient Characteristics
7BR.21 Patient Characteristics
8NCIC CTG BR.21 Best Response (N638)
9BR.21 Summary of Treatment Effect Response
10BR.21 Summary of Treatment Effect Response
NOT Significant EGFR Status (Trend)
PS
Prior platinum Prior response
Number of prior regimens
11BR.21 Progression Free Survival
Months
Adjusted for stratification factors (except
centre) AND EGFR status
12BR.21 Overall Survival
Adjusted for stratification factors (except
centre) AND EGFR status
Adjusted for stratification factors (except
centre) AND EGFR status
13Secondary EndpointsMedian Time to Deterioration
and PFS (weeks)
14EGFR 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???
15DEFINITION OF BENEFIT
- Response
- Survival
- Symptom improvement
- Any permutation and combination of the above
16Tumor Response (CRPR)Not a Good Surrogate for
Clinical Benefit with Erlotinib
17BR.21 Summary of Treatment Effect Survival
significant predictor in the multivariate
analysis.
18Tumor Response by Gender
19Question Is there clinical benefit with
erlotinib in males? A. Yes
20Survival for Females
21Survival for Males
22Tumor Response by Histology
23Question Is there clinical benefit with
erltoinib in squamous cell carcinomas? A. Yes
24Survival for Adenocarcinomas
25Survival for Squamous Cell Ca.
26Tumor Response by Smoking Status
27Question Is there clinical benefit with
erlotinib in current/ex-smokers? A. Yes
28Survival for Non-Smokers
29Survival for Current/Ex-Smokers
30Question Is the survival advantage lost for
patients who continue to smoke? A. Unclear
31Current Smokers
32Ex-Smokers
Note Incomplete information about when patients
stopped smoking
33Question Is there a survival advantage for
male smokers with squamous cell carcinoma? A.
Yes
34Current/Ex-Smoking Males with Squamous Cell
Histology
35Response Rates by Ethnicity
36Question Is there clinical benefit with
erlotinib in non-Orientals? A. Yes
37Oriental Ethnicity
38Non-Oriental Ethnicity
39BR.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
40Tarceva - 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
41Acknowledgements
- 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..
42Thank 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