1. NDA 21-399 ZD1839 for Treatment of NSCLC FDA Review Division of Oncology Drug Products

2. 9/24/02ODAC Presentation: NDA 21-3992 FDA ZD1839 NDA Review Team

3. 9/24/02ODAC Presentation: NDA 21-3993 Outline of FDA Presentation Regulatory Overview and Critical Issues Regulatory Overview and Critical Issues Grant Williams, MD Medical Review Findings Medical Review Findings Martin Cohen, MD Statistical Review Findings Statistical Review Findings Rajeshwari Sridhara, PhD Summary and Introduction of Questions Summary and Introduction of Questions Grant Williams, MD

4. 9/24/02ODAC Presentation: NDA 21-3994 Study Results 1. Claim of symptom improvement from a study without a control arm 2. Response rate (RR) of 10% in 139 patients with refractory NSCLC 3. No clinical benefit in two large controlled studies of first-line treatment of NSCLC 4. In view of #3, is the 10% RR in refractory NSCLC reasonably likely to predict clinical benefit?

5. 9/24/02ODAC Presentation: NDA 21-3995 Efficacy requirement for regular approval 1962 law: substantial evidence of efficacy from well controlled clinical trials 1962 law: substantial evidence of efficacy from well controlled clinical trials Efficacy is defined as clinical benefit Efficacy is defined as clinical benefit

6. 9/24/02ODAC Presentation: NDA 21-3996 DODP: Endpoints for Approval Approvals not based on Survival : 67% (37/55) excluding accelerated approvals 67% (37/55) excluding accelerated approvals 73% (48/66) of all approvals 73% (48/66) of all approvals

7. 9/24/02ODAC Presentation: NDA 21-3997 Examples of Approvals Based on Tumor-Related Symptoms Symptoms from obstructive esophageal cancer or lung cancer Symptoms from obstructive esophageal cancer or lung cancer Symptomatic prostate cancer Symptomatic prostate cancer Symptomatic cutaneous KS or CTCL Symptomatic cutaneous KS or CTCL Bone morbidity from metastatic cancer Bone morbidity from metastatic cancer

8. 9/24/02ODAC Presentation: NDA 21-3998 Problems with AZ symptom benefit claims No concurrent control No concurrent control Confounding palliative medications Confounding palliative medications Response correlation: Response correlation: Patient and observer bias Patient and observer bias Assessment bias Assessment bias Shared baseline prognostic factors (known and unknown) Shared baseline prognostic factors (known and unknown)

9. 9/24/02ODAC Presentation: NDA 21-3999 Accelerated approval Serious or life-threatening disease Serious or life-threatening disease Drug must provide benefit over available therapy Drug must provide benefit over available therapy Surrogate endpoint may be used Surrogate endpoint may be used Surrogate endpoint must be reasonably likely to predict clinical benefit Surrogate endpoint must be reasonably likely to predict clinical benefit Post marketing studies must verify clinical benefit Post marketing studies must verify clinical benefit

10. 9/24/02ODAC Presentation: NDA 21-39910 DODP Accelerated Approval Using Response Rates

11. 9/24/02ODAC Presentation: NDA 21-39911 Evidence for Accelerated Approval Substantial evidence from well controlled clinical trials regarding a surrogate endpoint Substantial evidence from well controlled clinical trials regarding a surrogate endpoint NOT: Borderline evidence regarding a clinical benefit endpoint NOT: Borderline evidence regarding a clinical benefit endpoint

12. 9/24/02ODAC Presentation: NDA 21-39912 Accelerated approval Serious or life-threatening disease Serious or life-threatening disease Drug must provide benefit over available therapy Drug must provide benefit over available therapy Surrogate endpoint may be used Surrogate endpoint may be used Surrogate endpoint must be reasonably likely to predict clinical benefit Surrogate endpoint must be reasonably likely to predict clinical benefit Post marketing studies must verify clinical benefit Post marketing studies must verify clinical benefit

13. 9/24/02ODAC Presentation: NDA 21-39913 Drug must provide benefit over available therapy Single arm trial design (all patients receive ZD1839) dictates study of patients with no available therapy Single arm trial design (all patients receive ZD1839) dictates study of patients with no available therapy Drugs are currently available for first-line and second-line treatment of NSCLC Drugs are currently available for first-line and second-line treatment of NSCLC The single arm design of Study 039 restricts the accelerated approval analysis to third-line NSCLC (139 patients) The single arm design of Study 039 restricts the accelerated approval analysis to third-line NSCLC (139 patients)

14. 9/24/02ODAC Presentation: NDA 21-39914 Reasonably likely to predict clinical benefit This is a judgement based on all available evidence This is a judgement based on all available evidence A response rate of about 10% has supported some AA’s (e.g., irinotecan) A response rate of about 10% has supported some AA’s (e.g., irinotecan) Lack of clinical benefit in large, randomized first-line studies must be considered Lack of clinical benefit in large, randomized first-line studies must be considered

15. Medical Review Findings Martin Cohen, MD

16. 9/24/02ODAC Presentation: NDA 21-39916 FDA Approved Drugs: NSCLC Stage IIIB/IV First line - paclitaxel/cisplatin gemcitabine/cisplatin gemcitabine/cisplatin vinorelbine + cisplatin vinorelbine + cisplatin Second line - docetaxel

17. NSCLC Stage IIIB/IV Submitted ZD1839 Clinical Trials Trial 39 - Third-line trial for accelerated approval Trial 39 - Third-line trial for accelerated approval Trial 16 - Supporting second-line trial Trial 16 - Supporting second-line trial INTACT 1 and 2 - First-line trials to demonstrate clinical benefit INTACT 1 and 2 - First-line trials to demonstrate clinical benefit

18. Trial Designs Phase II, Randomized, Double-Blind ZD1839 250 mg/day versus versus ZD1839 500 mg/day ZD1839 500 mg/day

19. Trial 39 - Efficacy Endpoints Co-primary: Response rate Response rate Disease related symptom improvement Disease related symptom improvement (Assessment difficulty was recognized)

20. 9/24/02ODAC Presentation: NDA 21-39920 Trial 39 ITT Population n=216

21. 9/24/02ODAC Presentation: NDA 21-39921 Trial 39 Pts refractory or intolerant

22. 9/24/02ODAC Presentation: NDA 21-39922 Trial 39 Responder Characteristics

23. 9/24/02ODAC Presentation: NDA 21-39923 Trial 39 Responder Characteristics

24. Symptom Assessment Problems - Patients and caregivers are unblinded - Patients and caregivers are unblinded - Patients are informed of response - Patients are informed of response - No prospective plan for managing - No prospective plan for managing concomitant medication concomitant medication

25. Concomitant Medication Narcotics Narcotics Bronchodilators Bronchodilators Antidepressants/Anxiolytics Antidepressants/Anxiolytics Oxygen Oxygen Prednisone Prednisone Transfusions/Erythropoietin Transfusions/Erythropoietin Antibiotics Antibiotics Cough Syrup Cough Syrup

26. 9/24/02ODAC Presentation: NDA 21-39926 Trial 16 ITT Population n=209

27. 9/24/02ODAC Presentation: NDA 21-39927 Trial 16: Prior Chemotherapy

28. 9/24/02ODAC Presentation: NDA 21-39928 Trial 16 Objective Response Rate

29. 9/24/02ODAC Presentation: NDA 21-39929 Responder Characteristics

30. 9/24/02ODAC Presentation: NDA 21-39930 Response Rate and Chemotherapy Progression

31. 9/24/02ODAC Presentation: NDA 21-39931 Trials 39 & 16 AE’s

32. 9/24/02ODAC Presentation: NDA 21-39932 Response Rates

33. 9/24/02ODAC Presentation: NDA 21-39933 Trial 39 Responding Patients Responders constitute a patient population enriched for slowly growing, relatively non-biologically aggressive cancers. Responders constitute a patient population enriched for slowly growing, relatively non-biologically aggressive cancers. Median time from diagnosis to randomization was 19.5 months Median time from diagnosis to randomization was 19.5 months Responders were predominantly P.S. 0-1 females with adenocarcinomas. Responders were predominantly P.S. 0-1 females with adenocarcinomas.

34. 9/24/02ODAC Presentation: NDA 21-39934 Symptom Improvement Problems in Interpretation Not blinded (no comparator regimen) Not blinded (no comparator regimen) Concomitant medications Concomitant medications Drug dose and schedule information not collected Drug dose and schedule information not collected ? bias in responders ? bias in responders

35. NDA 21-399: ZD1839 for NSCLC Statistical Review Findings Rajeshwari Sridhara, Ph.D.

36. 9/24/02ODAC Presentation: NDA 21-39936 Major Concerns in Trial IL0039 Trial Design: Single Arm Trial to Eliminate < 5% Response; Trial sized to independently evaluate efficacy in the two ZD1839 treatment arms (250 mg and 500 mg) Trial Design: Single Arm Trial to Eliminate < 5% Response; Trial sized to independently evaluate efficacy in the two ZD1839 treatment arms (250 mg and 500 mg) Heterogeneity of patient population (third and second line patients) Heterogeneity of patient population (third and second line patients) No Comparative Control Arm (no non-ZD1839 arm) No Comparative Control Arm (no non-ZD1839 arm)

37. 9/24/02ODAC Presentation: NDA 21-39937 Objective Tumor Response 250 mg + 500 mg ZD1839 Treatment Arms (Third Line Patients Only): 250 mg + 500 mg ZD1839 Treatment Arms (Third Line Patients Only): Total 14/139 ( 10.1 %) responses Total 14/139 ( 10.1 %) responses 95% C.I.: 5.6 %, 16.3% 95% C.I.: 5.6 %, 16.3%

38. 9/24/02ODAC Presentation: NDA 21-39938 Symptom Improvement - LCS Score Not atA littleSome-QuiteVery all bit whata lotmuch all bit whata lotmuch 1. I have been short of breath 0 1 2 3 4 2. I am losing weight 0 1 2 3 4 3. My thinking is clear 0 1 2 3 4 4. I have been coughing 0 1 2 3 4 5. I have a good appetite 0 1 2 3 4 6. I feel tightness in my chest 0 1 2 3 4 7. Breathing is easy for me 0 1 2 3 4

39. 9/24/02ODAC Presentation: NDA 21-39939 Symptom Improvement - LCS Score Not atA littleSome-QuiteVery all bit whata lotmuch all bit whata lotmuch 1. I have been short of breath 0 1 2 3 4 2. I am losing weight 0 1 2 3 4 3. My thinking is clear 0 1 2 3 4 4. I have been coughing 0 1 2 3 4 5. I have a good appetite 0 1 2 3 4 6. I feel tightness in my chest 0 1 2 3 4 7. Breathing is easy for me 0 1 2 3 4 0 28 0 28

40. 9/24/02ODAC Presentation: NDA 21-39940 Symptom Improvement - LCS Score Not atA littleSome-QuiteVery all bit whata lotmuch all bit whata lotmuch 1. I have been short of breath 0 1 2 3 4 2. I am losing weight 0 1 2 3 4 3. My thinking is clear 0 1 2 3 4 4. I have been coughing 0 1 2 3 4 5. I have a good appetite 0 1 2 3 4 6. I feel tightness in my chest 0 1 2 3 4 7. Breathing is easy for me 0 1 2 3 4 0 28 0 28 Baseline Score = 24

41. 9/24/02ODAC Presentation: NDA 21-39941 Symptom Improvement - LCS Score Not atA littleSome-QuiteVery all bit whata lotmuch all bit whata lotmuch 1. I have been short of breath 0 1 2 3 4 2. I am losing weight 0 1 2 3 4 3. My thinking is clear 0 1 2 3 4 4. I have been coughing 0 1 2 3 4 5. I have a good appetite 0 1 2 3 4 6. I feel tightness in my chest 0 1 2 3 4 7. Breathing is easy for me 0 1 2 3 4 0 28 0 28 Baseline Score= 24Improved Score = 26

42. 9/24/02ODAC Presentation: NDA 21-39942 Symptom Improvement Rate 250 mg and 500 mg ZD1839 Treatment Arms (Third line patients only): 250 mg and 500 mg ZD1839 Treatment Arms (Third line patients only): 45/139 (32.4 %) with symptom improvement per sponsor definition of improvement on the LCS scale 45/139 (32.4 %) with symptom improvement per sponsor definition of improvement on the LCS scale

43. 9/24/02ODAC Presentation: NDA 21-39943 Patient LCS Profile - An Example

44. 9/24/02ODAC Presentation: NDA 21-39944 Patient LCS Profile - An Example 1. Short of Breath 2. Losing Weight 3. Thinking is Clear 4. Been Coughing 5. Good Appetite 6. Tightness in Chest 7. Breathing Easy

45. 9/24/02ODAC Presentation: NDA 21-39945 % of Patients Evaluated Over Time

46. 9/24/02ODAC Presentation: NDA 21-39946 Critical Issues Efficacy with respect to Objective Tumor Response with ZD1839 could be as low as 5.6% (lower 95% CL = 5.6%). Efficacy with respect to Objective Tumor Response with ZD1839 could be as low as 5.6% (lower 95% CL = 5.6%). Symptom Improvement not interpretable without control data. Symptom Improvement not interpretable without control data. Symptom Improvement possibly confounded by concomitant medication effect and patient characteristics Symptom Improvement possibly confounded by concomitant medication effect and patient characteristics

47. 9/24/02ODAC Presentation: NDA 21-39947 Results of Randomized, Controlled, Phase III Studies in First-line NSCLC Patients Study IL0014: Study IL0014: Gemcitabine + Cisplatin + ZD1839 250 mg; N = 365 Gemcitabine + Cisplatin + ZD1839 250 mg; N = 365 Gemcitabine + Cisplatin + ZD1839 500 mg; N = 365 Gemcitabine + Cisplatin + ZD1839 500 mg; N = 365 Gemcitabine + Cisplatin + Placebo; N = 363 Gemcitabine + Cisplatin + Placebo; N = 363

48. 9/24/02ODAC Presentation: NDA 21-39948 250 mg vs. Placebo: HR 1.1 (0.9, 1.3), P-value 0.4382 500 mg vs. Placebo: HR 1.1 (0.9, 1.3), P-value 0.3041

49. 9/24/02ODAC Presentation: NDA 21-39949 250 mg vs. Placebo: HR 1.0 (0.8, 1.2) 500 mg vs. Placebo: HR 0.9 (0.8, 1.1)

50. 9/24/02ODAC Presentation: NDA 21-39950 Tumor Response and One-year Survival Rates in Trial IL0014 Treatment ArmResponse Rate (95% C.I.) % KM Survival Estimate at 1 yr (S.E.) Chemo + ZD1839 250 mg 50.1% (44.7%, 55.6%) 43.75 (2.61) Chemo + ZD1839 500 mg 49.7% (44.2%, 55.2%) 41.51(2.59) Chemo + Placebo 44.8% (39.3%, 50.4%) 44.87 (2.64)

51. 9/24/02ODAC Presentation: NDA 21-39951 Results of Randomized, Controlled, Phase III Studies in First-line NSCLC Patients Study IL0017: Study IL0017: Taxol + Carboplatin + ZD1839 250 mg; N = 347 Taxol + Carboplatin + ZD1839 250 mg; N = 347 Taxol + Carboplatin + ZD1839 500 mg; N = 345 Taxol + Carboplatin + ZD1839 500 mg; N = 345 Taxol + Carboplatin + Placebo; N = 345 Taxol + Carboplatin + Placebo; N = 345

52. 9/24/02ODAC Presentation: NDA 21-39952 250 mg vs. Placebo: HR 1.0 (0.9, 1.2), P-value 0.6429 500 mg vs. Placebo: HR 1.0 (0.8, 1.2), P-value 0.6710

53. 9/24/02ODAC Presentation: NDA 21-39953 250 mg vs. Placebo: HR 0.85 (0.70, 1.03) 500 mg vs. Placebo: HR 0.86 (0.72, 1.04)

54. 9/24/02ODAC Presentation: NDA 21-39954 Tumor Response and One-year Survival Rates in Trial IL0017 Treatment ArmResponse Rate (95% C.I.) % KM Survival Estimate at 1 yr (S.E.) Chemo + ZD1839 250 mg 35.0% (29.6%, 40.6%) 37.57 (2.60) Chemo + ZD1839 500 mg 32.1% (27.0%, 37.7%) 41.89 (2.67) Chemo + Placebo 33.6% (28.1%, 39.3%) 42.22 (2.66)

55. 9/24/02ODAC Presentation: NDA 21-39955 Results of Phase III Studies No Statistically Significant Difference with respect to Overall Survival between ZD1839 treated group and Placebo treated group in the two well conducted, placebo controlled, randomized studies in over 2000 patients. No Statistically Significant Difference with respect to Overall Survival between ZD1839 treated group and Placebo treated group in the two well conducted, placebo controlled, randomized studies in over 2000 patients. No difference between ZD1839 treated arm and Placebo treated arm with respect to secondary endpoints including response rate and time to progression in both the studies. No difference between ZD1839 treated arm and Placebo treated arm with respect to secondary endpoints including response rate and time to progression in both the studies.

56. Summary of FDA Findings Grant Williams, MD

57. 9/24/02ODAC Presentation: NDA 21-39957 Study Results 1. Claim of symptom improvement from a study without a control arm 2. Response rate (RR) of 10% in 139 patients with refractory NSCLC 3. No clinical benefit in two large controlled studies of first-line treatment of NSCLC 4. In view of #3, is the 10% RR in refractory NSCLC reasonably likely to predict clinical benefit?

58. 9/24/02ODAC Presentation: NDA 21-39958 Questions to the Committee 1. Can symptom improvements claimed for ZD1839 be adequately assessed without a control arm? 2. Given negative studies in first-line treatment of NSCLC, is the 10% RR in refractory NSCLC reasonably likely to predict clinical benefit? 3. Discuss expanded access 4. Discuss design of additional trials.