Clinical Efficacy Data Review of Study NCIC CTG PA.3

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Clinical Efficacy DataReview of Study NCIC CTG
PA.3

• Gary M. Clark, PhD
• Vice President
• Biostatistics and Data Management
• OSI Pharmaceuticals, Inc.

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Statistical Considerationsfor Data Analysis

• Statistical analysis plan submitted to FDA before
  database lock and unblinding
• Agreement with FDA reached on primary analysis
• Stratified log-rank test for overall survival
• Protocol PS, extent of disease, pain intensity
• FDA request PS, extent of disease
• All randomized patients included (ITT population)
• No interim efficacy analyses planned or performed

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Patient CharacteristicsITT Population

• Baseline characteristics generally well balanced
  between arms

Characteristic Tarceva gemcitabinen 285 Placebo gemcitabinen 284
Median age, year 63 64
Female/male, 52/48 43/57
PS 0/1/2, 30/51/19 30/52/18
Locally advanced/metastatic, 24/76 25/75
Pain 20/ gt 20/ unknown, 46/51/3 45/53/2
Measurable disease, 94 92
US/Canada/Rest of World, 38/20/42 36/21/43
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Patients Who Did Not Receive Assigned Protocol
Therapy

• 7 patients did not receive any protocol therapy
• 3 in Tarceva gemcitabine arm
• 4 in placebo gemcitabine arm
• 2 patients did not receive the assigned treatment
• 1 randomized to placebo received Tarceva
• 1 randomized to Tarceva received placebo
• All randomized patients (ITT population) included
  in efficacy analyses
• Safety analyses performed on as-treated
  population

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Ineligible Patients (n 18)FDA Review Based on
Primary Diagnosis
Reason for ineligibility Tarceva gemcitabine Placebo gemcitabine
Adenocarcinoma of the Ampulla of Vater 2 2
Different primary site (gastric 2, CRC 1) 3 0
Acinar cell carcinoma of the pancreas 1 1
Pathology report not available 2 0
Pathology report not conclusive 0 2
CT scan report not available 2 1
CT scan report not conclusive 0 2
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Primary Efficacy Endpoint Overall Survival in
the ITT Population
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Overall SurvivalITT Population (485 Deaths)
HR 0.80 (95 CI 0.67, 0.96), p 0.018

• ? 20 reduction in the risk of death
• ? 25 increase in survival

Adjusted for PS and extent of disease at
randomization
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Overall SurvivalITT Population (485 Deaths)
HR 0.80 (95 CI 0.67, 0.96), p 0.018
Tarceva gemcitabine Placebo gemcitabine
Median survival, months 6.24 5.91
1-year survival 23 17
Adjusted for PS and extent of disease at
randomization
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Overall SurvivalRobustness AnalysesITT
Population
Analysis HR (95 CI) p-value
Stratified log-rank (485 deaths) 0.80 (0.67, 0.96) 0.018
Cox model with stratification factors gender 0.80 (0.67, 0.96) 0.015
Cox model with stratification factors other prognostic factors (gender, pain intensity, age, race, prior chemotherapy, region, and baseline albumin) 0.81 (0.67, 0.97) 0.023
Stratified log-rank, censor at 1st anticancer therapy (341 deaths) 0.80 (0.64, 0.99) 0.039
Stratified log-rank (381 deaths) 0.80 (0.65, 0.98) 0.034
Stratified log-rank (551 deaths June 2005) 0.81 (0.68, 0.96) 0.016
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Overall Survival100 mg Cohort (444 Deaths)
HR 0.81 (95 CI 0.67, 0.98), p 0.028
? 23 increase in survival
Tarceva gemcitabine Placebo gemcitabine
Median survival, months 6.37 5.95
1-year survival 23 17
Adjusted for PS and extent of disease at
randomization
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Overall SurvivalRobustness Analyses 100 mg
Cohort
Analysis HR (95 CI) p-value
Stratified log-rank (444 deaths) 0.81 (0.67, 0.98) 0.028
Cox model with stratification factors gender 0.81 (0.67, 0.98) 0.028
Cox model with stratification factors other prognostic factors (gender, pain intensity, age, race, prior chemotherapy, region, and baseline albumin) 0.82 (0.68, 1.00) 0.048
Stratified log-rank, censor at 1st anticancer therapy (313 deaths) 0.80 (0.64, 1.00) 0.050
Stratified log-rank (381 deaths) 0.82 (0.67, 1.01) 0.059
Stratified log-rank (504 deaths June 2005) 0.82 (0.69, 0.98) 0.028
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Sensitivity Survival Analyses Using Stratified
Log-Rank Tests100 mg Cohort
N Deaths HR 95 CI p-value
Database as of Jan 2004
As-treated population 515 440 0.81 0.67, 0.97 0.025
Eligible patients 503 432 0.81 0.67, 0.99 0.036
Eligible patients in as-treated population 497 428 0.81 0.67, 0.98 0.031

Database as of June 2005
As-treated population 515 500 0.82 0.69, 0.98 0.026
Eligible patients 503 487 0.82 0.69, 0.99 0.036
Eligible patients in as-treated population 497 483 0.83 0.69, 0.99 0.038
As per FDA review of primary diagnosis Analyses
adjusted for PS and extent of disease at
randomization
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Robustness of Survival Benefit

• The survival benefit for Tarceva
• Does not depend on the statistical
  analyticalapproach used
• Remains statistically significant in multivariate
  analyses
• Cannot be explained by benefit from subsequent
  anticancer therapy
• Persists with additional follow-up
• Persists when ineligible patients are excluded

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Secondary Efficacy Endpoints
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Progression-Free Survival100 mg Cohort
HR 0.77 (95 CI 0.64, 0.93), p 0.006
Tarceva gemcitabine Placebo gemcitabine
Median PFS, months 3.81 3.55
6-month PFS 33 25
Adjusted for PS and extent of disease at
randomization
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Tumor ResponsePatients with Measurable
Disease100 mg Cohort
patients patients
Tarceva gemcitabinen 244 Placebo gemcitabinen 241
CR PR 8.6 7.9
Stable disease (SD) 50.4 41.5
CR PR SD 59.0 49.4
PD/NE 41.0 50.6
Median duration of response in weeks (range) 23.9(3.7, 56.0) 23.3(6.7, 65.3)
p 0.036
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EGFR Status by Immunohistochemistry
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Overall Survival by EGFR Status100 mg Cohort
EGFR-Positive Patients
EGFR-Negative Patients
HR 0.71 (95 CI 0.42, 1.19)
HR 0.78 (95 CI 0.47, 1.30)
p-value (interaction) 0.826
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Quality of Life (QoL)

• Objective
• To evaluate the impact of adding Tarceva to
  gemcitabine on the patients self-reported
  quality of life
• Exploratory, hypothesis-generating analyses

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EORTC QLQ-C30Validated Quality of Life
Questionnaire

• Global assessment
• Functional domains
• Physical
• Role
• Emotional
• Cognitive
• Social

• Symptom domains
• Fatigue
• Nausea and vomiting
• Pain
• Single items
• Dyspnea
• Sleep
• Appetite
• Constipation
• Diarrhea
• Financial

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EORTC QLQ-C30Quality of Life Results

• Global assessment NS
• Functional domains
• Physical NS
• Role NS
• Emotional NS
• Cognitive NS
• Social NS

• Symptom domains
• Fatigue NS
• Nausea and vomiting NS
• Pain NS
• Single items
• Dyspnea NS
• Sleep NS
• Appetite NS
• Constipation NS
• Diarrhea lt 0.05
• Financial NS

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Mean Change from Baseline inDiarrhea Single Item
Scale Over Time100 mg Cohort
Tarceva, n 206 167 127 109 81 63 41 33 23 22 17 14
13 Placebo, n 202 156 94 82 70 50 37 32 21 18 13
8 5
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Mean Change from Baseline inSocial Functioning
Domain Over Time100 mg Cohort
Tarceva, n 206 169 127 111 81 63 42 33 25 22 17 14
13Placebo, n 202 158 95 83 70 50 38 32 21 18 13
8 5
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Mean Change from Baseline inGlobal Quality of
Life Over Time100 mg Cohort
Tarceva, n 206 169 127 111 80 63 42 33 25 21 17 14
13Placebo, n 202 157 95 83 69 50 37 32 21 18 13
8 5
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Efficacy Summary100 mg Cohort
Tarceva treatment in combination with gemcitabine
resulted in

• Statistically significant 23 improvement in
  overall survival (HR 0.81)
• Statistically significant 30 improvement in PFS
  (HR 0.77)
• No difference in response rates, but an
  improvement in disease control rate (CRPRSD)
• No detrimental effect on global QoL compared with
  placebo/gemcitabine