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IRESSA ® (ZD1839) Monotherapy for Non-Small Cell Lung Cancer (NSCLC)

ONCOLOGY. IRESSA ® (ZD1839) Monotherapy for Non-Small Cell Lung Cancer (NSCLC). Oncologic Drugs Advisory Committee Meeting September 24, 2002. IRESSA ® Introduction. George Blackledge, MD Clinical Vice President, Oncology AstraZeneca Pharmaceuticals. IRESSA ® Agenda for Today’s Meeting.

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IRESSA ® (ZD1839) Monotherapy for Non-Small Cell Lung Cancer (NSCLC)

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  1. ONCOLOGY IRESSA®(ZD1839)Monotherapy for Non-Small Cell Lung Cancer (NSCLC) Oncologic Drugs Advisory Committee Meeting September 24, 2002

  2. IRESSA®Introduction George Blackledge, MD Clinical Vice President, Oncology AstraZeneca Pharmaceuticals

  3. 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

  4. Jose Baselga, MD Chairman, Medical Oncology Vall d'Hebron University Hospital Barcelona, Spain David Cella, PhD Director, Center on OutcomesResearch and Education Northwestern University Evanston, IL Gary Donaldson, PhD Professor, Department of Anesthesiology University of Utah School of Medicine Salt Lake City, UT Mark Kris, MD Chief, Thoracic Oncology Memorial Sloan-Kettering Cancer Center New York, NY Thomas Lynch, MD Associate Professor of Medicine Massachusetts General Hospital Boston, MA Experts Available for Q&A

  5. Experts Available From AstraZeneca Steve Averbuch, MD Andrea Kay, MD David McKillop, PhD Judith Ochs, MD Graham Richmond, MSc Mark Scott, PhD Mark Steinberg, MD Helen Swaisland, BSc Alan Wakeling, PhD Michael Wolf, MSc

  6. IRESSA® 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

  7. 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.

  8. How Did We Get Here? IRESSA® • Molecular targeted agents 1990 discovery program • ZD1839 molecule discovered 1994 • Healthy volunteer trials 1997

  9. CI-9 K K K K EGFR Signal Transduction in Tumor Cells R R R R Gene transcription and cell cycle progression myc cyclin D1 Jun Fos

  10. CI-10 RAS RAF R P P P P K K SOS R K GRB2 PI3-K P P K MEK AKT MAPK Inhibition of apoptosis Proliferation Metastasis Angiogenesis EGFR Signal Transduction in Tumor Cells R R Gene transcription and cell cycle progression myc cyclin D1 Jun Fos

  11. IRESSA® 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

  12. IRESSA® Inhibits Growth of A549 Xenograft Tumors (NSCLC) IRESSA 200 mg/kg, po days 10 - 72 IRESSA 200 mg/kg, po days 10 - 30 Vehicle 0.8 0.7 0.6 0.5 Mean tumor volume, cm3 0.4 0.3 0.2 0.1 0 0 20 40 60 80 Day

  13. Clinical Pharmacokinetics (N = 535) • Bioavailability ~ 60% • No clinically significant effect of food • Mean t½ = 41 hours • Steady state achieved within 7 to 10 days Daily oral dosing administration schedule

  14. IRESSA® 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 §Separate Fast Track designations by FDA

  15. 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

  16. X-rays of NSCLC Patient Pre- and Post-Treatment With IRESSA®(400 mg/day) Prior to treatment After 14 days treatment

  17. IRESSA® 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 §Separate Fast Track designations by FDA

  18. Rationale for Monotherapy Trials 39 and 16 • No approved therapy for 3rd-line NSCLC patients • Clinical need • Objective response • Symptom improvement • Well-tolerated therapy

  19. Results Trials 39 and 16 • 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

  20. IRESSA® 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 §Separate Fast Track designations by FDA

  21. 1st-Line Combination Therapy Trials 14 and 17 • 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

  22. 1st-Line Combination Trial Results • 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 additional safety issues

  23. 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

  24. “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

  25. Randomized, Controlled Trials in NSCLC Trial DesignRandomization 3rd line Iressa vs BSC 2nd 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 placebo AZ (Japan) - actively recruiting NCI / NCI-C / EORTC – to start 4Q02

  26. IRESSA® 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 §Separate Fast Track designations by FDA

  27. IRESSA® 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

  28. IRESSA® 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

  29. IRESSA® 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 §Separate Fast Track designations by FDA

  30. 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?

  31. 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?

  32. 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.

  33. 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.

  34. IRESSA® • High unmet need in target population • Consistent response rate • Correlated symptomatic benefit • Well tolerated, easily administered

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