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IRESSA®
(ZD1839) Monotherapy for Non-Small Cell
Lung Cancer (NSCLC)
IRESSA®
(ZD1839) Monotherapy for Non-Small Cell
Lung Cancer (NSCLC)
Oncologic Drugs
Advisory Committee Meeting September 24, 2002
Oncologic Drugs
Advisory Committee Meeting September 24, 2002
ONCOLOGY
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IRESSA® IntroductionIRESSA®
Introduction
George Blackledge, MD
Clinical Vice President, Oncology
AstraZeneca Pharmaceuticals
George Blackledge, MD
Clinical Vice President, Oncology
AstraZeneca Pharmaceuticals
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IRESSA® Agenda for Today’s Meeting
IRESSA® Agenda for Today’s Meeting
Introduction George Blackledge, MD
Refractory NSCLC Frances A. Shepherd, MD
Clinical efficacy Ronald B. Natale, MD
Safety profile Alan B. Sandler, MD
Summary George Blackledge, MD
Introduction George Blackledge, MD
Refractory NSCLC Frances A. Shepherd, MD
Clinical efficacy Ronald B. Natale, MD
Safety profile Alan B. Sandler, MD
Summary George Blackledge, MD
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Experts Available for Q&AExperts Available for Q&A
Jose Baselga, MDChairman, Medical OncologyVall d'Hebron University HospitalBarcelona, Spain
David Cella, PhDDirector, Center on OutcomesResearch and Education Northwestern UniversityEvanston, IL
Gary Donaldson, PhDProfessor, Department of AnesthesiologyUniversity of Utah School of MedicineSalt Lake City, UT
Jose Baselga, MDChairman, Medical OncologyVall d'Hebron University HospitalBarcelona, Spain
David Cella, PhDDirector, Center on OutcomesResearch and Education Northwestern UniversityEvanston, IL
Gary Donaldson, PhDProfessor, Department of AnesthesiologyUniversity of Utah School of MedicineSalt Lake City, UT
Mark Kris, MDChief, Thoracic OncologyMemorial Sloan-Kettering Cancer CenterNew York, NY
Thomas Lynch, MDAssociate Professor of MedicineMassachusetts General HospitalBoston, MA
Mark Kris, MDChief, Thoracic OncologyMemorial Sloan-Kettering Cancer CenterNew York, NY
Thomas Lynch, MDAssociate Professor of MedicineMassachusetts General HospitalBoston, MA
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Experts Available From AstraZeneca Experts Available From AstraZeneca
Steve Averbuch, MDAndrea Kay, MDDavid McKillop, PhDJudith Ochs, MDGraham Richmond, MScMark Scott, PhDMark Steinberg, MDHelen Swaisland, BScAlan Wakeling, PhDMichael Wolf, MSc
Steve Averbuch, MDAndrea Kay, MDDavid McKillop, PhDJudith Ochs, MDGraham Richmond, MScMark Scott, PhDMark Steinberg, MDHelen Swaisland, BScAlan Wakeling, PhDMichael Wolf, MSc
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IRESSA® for 3rd-Line NSCLCIRESSA® for 3rd-Line NSCLC
High unmet need
– Thousands of patients each year
– Disease of symptoms
IRESSA
– Unprecedented activity in target population
– Symptom control
– Excellent tolerability
High unmet need
– Thousands of patients each year
– Disease of symptoms
IRESSA
– Unprecedented activity in target population
– Symptom control
– Excellent tolerability
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Demonstration of the Role of IRESSA®Demonstration of the Role of IRESSA®
IRESSA® 250 mg po daily can be used
in the 3rd-line treatment of patients
with locally advanced or metastatic
non-small cell lung cancer.
IRESSA® 250 mg po daily can be used
in the 3rd-line treatment of patients
with locally advanced or metastatic
non-small cell lung cancer.
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How Did We Get Here? IRESSA®
How Did We Get Here? IRESSA®
Molecular targeted agents 1990 discovery program
ZD1839 molecule discovered 1994
Healthy volunteer trials 1997
Molecular targeted agents 1990 discovery program
ZD1839 molecule discovered 1994
Healthy volunteer trials 1997
myc cyclin D1
Jun Fos
RRRR
RRRR
EGFR Signal Transduction in Tumor Cells EGFR Signal Transduction in Tumor Cells
K K
KK
Gene transcription and cell cycle progression
Gene transcription and cell cycle progression
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MetastasisAngiogenesis
myc cyclin D1
Jun Fos
RRRR
EGFR Signal Transduction in Tumor Cells EGFR Signal Transduction in Tumor Cells
K KRR
K
RR
K
Gene transcription and cell cycle progression
Gene transcription and cell cycle progression
MAPKMAPK
MEKMEK
RASRAS RAFRAF
SOSSOS
GRB2GRB2
Proliferation
PI3-KPI3-K
AKTAKT
Inhibition of apoptosis
PPPP
PPPP
PPPP
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IRESSA® Non-Clinical SummaryIRESSA® Non-Clinical Summary
IC50 (µM)
Selective enzyme inhibition
– EGFR (ErbB-1): 0.033
– Other cellular kinases > 3
EGFR autophosphorylation < 1 inhibition in tumor cell lines
Tumor cell growth inhibition
– EGF stimulated 0.054
– Basal 8.8
IC50 (µM)
Selective enzyme inhibition
– EGFR (ErbB-1): 0.033
– Other cellular kinases > 3
EGFR autophosphorylation < 1 inhibition in tumor cell lines
Tumor cell growth inhibition
– EGF stimulated 0.054
– Basal 8.8
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8060402000
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Day
Mea
n t
um
or
volu
me,
cm
3IRESSA® Inhibits Growth of
A549 Xenograft Tumors (NSCLC)IRESSA® Inhibits Growth of
A549 Xenograft Tumors (NSCLC)
IRESSA 200 mg/kg, po days 10 - 72IRESSA 200 mg/kg, po days 10 - 30Vehicle
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Clinical Pharmacokinetics (N = 535)
Clinical Pharmacokinetics (N = 535)
Bioavailability ~ 60%
No clinically significant effect of food
Mean t½ = 41 hours
Steady state achieved within 7 to 10 days
Bioavailability ~ 60%
No clinically significant effect of food
Mean t½ = 41 hours
Steady state achieved within 7 to 10 days
Daily oral dosing administration scheduleDaily oral dosing administration schedule
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Phase I clinical trials 1998
3rd-line monotherapy 2000(Trials 39 and 16)§
1st-line combination therapy 2000(Trials 14 and 17)§
Expanded Access Program (EAP) 2000
Phase I clinical trials 1998
3rd-line monotherapy 2000(Trials 39 and 16)§
1st-line combination therapy 2000(Trials 14 and 17)§
Expanded Access Program (EAP) 2000
IRESSA® Clinical Development ProgramIRESSA® Clinical Development Program
§Separate Fast Track designations by FDA§Separate Fast Track designations by FDA
Phase I clinical trials
1998
Phase I clinical trials
1998
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IRESSA® Phase I Safety and Activity (N = 289)
IRESSA® Phase I Safety and Activity (N = 289)
Safety profile
– Grade 1 - 2 skin, GI toxicity common
– Dose-limiting toxicity: reversible Grade 3 diarrhea at 800 to 1,000 mg daily
Striking symptom improvement in NSCLC Antitumor activity in NSCLC
– 10 objective responses in 100 patients
– 17 on study ≥ 6 months
Safety profile
– Grade 1 - 2 skin, GI toxicity common
– Dose-limiting toxicity: reversible Grade 3 diarrhea at 800 to 1,000 mg daily
Striking symptom improvement in NSCLC Antitumor activity in NSCLC
– 10 objective responses in 100 patients
– 17 on study ≥ 6 months
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Prior to treatmentPrior to treatment After 14 days treatmentAfter 14 days treatment
X-rays of NSCLC Patient Pre- and Post-Treatment With IRESSA®
(400 mg/day)
X-rays of NSCLC Patient Pre- and Post-Treatment With IRESSA®
(400 mg/day)
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IRESSA® Clinical Development ProgramIRESSA® Clinical Development Program
Phase I clinical trials 1998
3rd-line monotherapy 2000(Trials 39 and 16)§
1st-line combination therapy 2000(Trials 14 and 17)§
Expanded Access Program (EAP) 2000
Phase I clinical trials 1998
3rd-line monotherapy 2000(Trials 39 and 16)§
1st-line combination therapy 2000(Trials 14 and 17)§
Expanded Access Program (EAP) 2000
§Separate Fast Track designations by FDA§Separate Fast Track designations by FDA
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Rationale for Monotherapy Rationale for Monotherapy
No approved therapy for 3rd-line NSCLC patients
Clinical need
– Objective response
– Symptom improvement
– Well-tolerated therapy
No approved therapy for 3rd-line NSCLC patients
Clinical need
– Objective response
– Symptom improvement
– Well-tolerated therapy
Trials 39 and 16
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Results Results
Response rate 10% in Trial 39 with an additional 30% stable disease
Associated symptom improvement
Similar supportive data in Trial 16
Highly acceptable safety profile
Response rate 10% in Trial 39 with an additional 30% stable disease
Associated symptom improvement
Similar supportive data in Trial 16
Highly acceptable safety profile
Trials 39 and 16
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IRESSA® Clinical Development ProgramIRESSA® Clinical Development Program
Phase I clinical trials 1998
3rd-line monotherapy 2000(Trials 39 and 16)§
1st-line combination therapy 2000(Trials 14 and 17)§
Expanded Access Program (EAP) 2000
Phase I clinical trials 1998
3rd-line monotherapy 2000(Trials 39 and 16)§
1st-line combination therapy 2000(Trials 14 and 17)§
Expanded Access Program (EAP) 2000
§Separate Fast Track designations by FDA§Separate Fast Track designations by FDA
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1st-Line Combination Therapy1st-Line Combination Therapy
Rationale– Novel mechanism of action – Objective responses in Phase I– Was seen as the next logical step in improving
outcome in NSCLC Trial design
– Previously untreated patients with advanced, unresectable NSCLC
– Standard combination chemotherapy ± IRESSA®
– Primary objective: survival
Rationale– Novel mechanism of action – Objective responses in Phase I– Was seen as the next logical step in improving
outcome in NSCLC Trial design
– Previously untreated patients with advanced, unresectable NSCLC
– Standard combination chemotherapy ± IRESSA®
– Primary objective: survival
Trials 14 and 17
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1st-Line Combination Trial Results1st-Line Combination Trial Results
Both trials – Representative of typical 1st-line populations – Well-balanced baseline patient and disease
characteristics
Both trials – Representative of typical 1st-line populations – Well-balanced baseline patient and disease
characteristics No difference in overall survival across treatment
arms in both trials Analysis of response rate and time to progression
showed no additional benefit for IRESSA® added to 2-drug chemotherapy
No difference in overall survival across treatment arms in both trials
Analysis of response rate and time to progression showed no additional benefit for IRESSA® added to 2-drug chemotherapy
No additional safety issues No additional safety issues
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IRESSA® 3rd-Line Monotherapy Benefit Distinct From Combination Trial Data
IRESSA® 3rd-Line Monotherapy Benefit Distinct From Combination Trial Data
Trials 14 and 17 outcomes are not germane to results demonstrated in 3rd-line NSCLC
– Different treatment setting
– Combination with chemotherapy rather than monotherapy
Lack of survival benefit in 1st-line does not negate responses and symptom improvement in 3rd-line
Trials 14 and 17 outcomes are not germane to results demonstrated in 3rd-line NSCLC
– Different treatment setting
– Combination with chemotherapy rather than monotherapy
Lack of survival benefit in 1st-line does not negate responses and symptom improvement in 3rd-line
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“With Genentech’s anti-VEGF announcement recently, SWOG’s evidence of interference by tamoxifen in the efficacy of breast cancer adjuvant therapy, and the IRESSA® results, I think we’re seeing a pattern emerge that is really (paradoxically) quite hopeful.
We’ve said that these new therapies are dramatically unlike chemotherapy but we’ve tried to develop them as if they were.
Now we know they’re not, and IRESSA has to be used following different paradigms.”
Larry Norton, MD
“With Genentech’s anti-VEGF announcement recently, SWOG’s evidence of interference by tamoxifen in the efficacy of breast cancer adjuvant therapy, and the IRESSA® results, I think we’re seeing a pattern emerge that is really (paradoxically) quite hopeful.
We’ve said that these new therapies are dramatically unlike chemotherapy but we’ve tried to develop them as if they were.
Now we know they’re not, and IRESSA has to be used following different paradigms.”
Larry Norton, MD
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Trial Design Randomization
3rd line Iressa vs BSC2nd line Iressa vs Taxotere
Taxotere +/- Iressa
1st line Iressa vs Navelbine(platinum-ineligible pts)Protocol final; to start 4Q02
Locally advanced Iressa vs placebo CT+RT Taxotere × 3 Randomize NCI (SWOG / Intergroup) – actively recruiting
Adjuvant Iressa vs placeboAZ (Japan) - actively recruiting NCI / NCI-C / EORTC – to start 4Q02
Randomized, Controlled Trials in NSCLCRandomized, Controlled Trials in NSCLC
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IRESSA® Clinical Development ProgramIRESSA® Clinical Development Program
Phase I clinical trials 1998
3rd-line monotherapy 2000(Trials 39 and 16)§
1st-line combination therapy 2000(Trials 14 and 17)§
Expanded Access Program (EAP) 2000
Phase I clinical trials 1998
3rd-line monotherapy 2000(Trials 39 and 16)§
1st-line combination therapy 2000(Trials 14 and 17)§
Expanded Access Program (EAP) 2000
§Separate Fast Track designations by FDA§Separate Fast Track designations by FDA
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IRESSA® Expanded Access ProgramIRESSA® Expanded Access Program
Rationale– Clinical benefit in Phase I– Satisfy patient and physician demand
Developed in close collaboration with– FDA – NORD – Patient advocates – Medical ethicists
Eligible population– Patients with advanced NSCLC and
no other treatment options
Rationale– Clinical benefit in Phase I– Satisfy patient and physician demand
Developed in close collaboration with– FDA – NORD – Patient advocates – Medical ethicists
Eligible population– Patients with advanced NSCLC and
no other treatment options
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IRESSA® Expanded Access ProgramIRESSA® Expanded Access Program
Confirmed unmet need in refractory NSCLC
~ 18,000 patients worldwide (2,000 per month)
~ 40% of patients continued IRESSA beyond 6 months
Confirmed unmet need in refractory NSCLC
~ 18,000 patients worldwide (2,000 per month)
~ 40% of patients continued IRESSA beyond 6 months
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IRESSA® Clinical Development ProgramIRESSA® Clinical Development Program
Phase I clinical trials 1998
3rd-line monotherapy 2000(Trials 39 and 16)§
1st-line combination therapy 2000(Trials 14 and 17)§
Expanded Access Program (EAP) 2000
Phase I clinical trials 1998
3rd-line monotherapy 2000(Trials 39 and 16)§
1st-line combination therapy 2000(Trials 14 and 17)§
Expanded Access Program (EAP) 2000
§Separate Fast Track designations by FDA§Separate Fast Track designations by FDA
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FDA Questions (1)FDA Questions (1)
The FDA believes the relevance of the symptom improvement data discussed above cannot be adequately evaluated without a randomized, blinded study with an adequate control arm (the two doses of ZD1839 show no difference in efficacy and are thus not adequate). Do you agree?
The FDA believes the relevance of the symptom improvement data discussed above cannot be adequately evaluated without a randomized, blinded study with an adequate control arm (the two doses of ZD1839 show no difference in efficacy and are thus not adequate). Do you agree?
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FDA Questions (2)FDA Questions (2)
Given the lack of clinical benefit in two large studies of ZD1839 in combination with standard first-line NSCLC chemotherapy, is the Study 0039 response rate of 10% in 139 patients with resistant or refractory NSCLC reasonably likely to predict ZD1839 clinical benefit in NSCLC?
Given the lack of clinical benefit in two large studies of ZD1839 in combination with standard first-line NSCLC chemotherapy, is the Study 0039 response rate of 10% in 139 patients with resistant or refractory NSCLC reasonably likely to predict ZD1839 clinical benefit in NSCLC?
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FDA Questions (3)FDA Questions (3)
More than 12,000 NSCLC patients have received ZD1839 under an Expanded Access Protocol. Please discuss what position FDA should take on ZD1839 expanded access if marketing approval of ZD1839 is not granted at this time.
More than 12,000 NSCLC patients have received ZD1839 under an Expanded Access Protocol. Please discuss what position FDA should take on ZD1839 expanded access if marketing approval of ZD1839 is not granted at this time.
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FDA Questions (4)FDA Questions (4)
Regardless of whether ZD1839 is granted accelerated approval for treating NSCLC, additional trials may be needed. Please discuss potential study designs to demonstrate that ZD1839 provides clinical benefit to NSCLC patients.
Regardless of whether ZD1839 is granted accelerated approval for treating NSCLC, additional trials may be needed. Please discuss potential study designs to demonstrate that ZD1839 provides clinical benefit to NSCLC patients.