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Gemzar in Combination with Carboplatin as Treatment for Women with Recurrent Ovarian Cancer March 13, 2006 Richard Ga

2. Agenda. Introduction and Objectives Management of Ovarian Cancer Clinical Efficacy of Gemzar/CarboplatinSafety Results and Patient Benefit Robustness of Efficacy Results Risk/Benefit Overview. 8002.01. Richard Gaynor, MD Vice President, Oncology Lilly Research

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Gemzar in Combination with Carboplatin as Treatment for Women with Recurrent Ovarian Cancer March 13, 2006 Richard Ga

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    1. Gemzar® in Combination with Carboplatin as Treatment for Women with Recurrent Ovarian Cancer March 13, 2006 Richard Gaynor, MD Vice President, Global Oncology Lilly Research Laboratories Oncologic Drugs Advisory Committee Presentation

    2. 2 Agenda Introduction and Objectives Management of Ovarian Cancer Clinical Efficacy of Gemzar/Carboplatin Safety Results and Patient Benefit Robustness of Efficacy Results Risk/Benefit Overview

    3. 3 Expert Participants Eli Lilly and Company Medical Richard Gaynor, MD Marek Kania, MD, MBA Martin Marciniak, PhD Allen Melemed, MD Regulatory Affairs Cheryl Beal Anderson, PharmD Colleen Mockbee, RPh Statistics James Symanowski, PhD Annamaria Zimmermann, MS

    4. 4 Ovarian Cancer Supplemental NDA

    5. 5 Gemzar sNDA Ovarian Cancer

    6. 6 Regulatory Background Historically, overall response rate has been primarily used in this setting. Lilly met with the FDA in late 2004 and reviewed the trial design and results. FDA agreed the data package met criteria for submission. Today we plan to discuss that the totality of the data which we feel supports full approval of Gem/Carbo for woman with recurrent ovarian cancer.Historically, overall response rate has been primarily used in this setting. Lilly met with the FDA in late 2004 and reviewed the trial design and results. FDA agreed the data package met criteria for submission. Today we plan to discuss that the totality of the data which we feel supports full approval of Gem/Carbo for woman with recurrent ovarian cancer.

    7. 7 Background on Gemzar Pyrimidine anti-metabolite with broad activity across numerous tumor types Over 1.3 million patients treated globally with Gemzar FDA regular approvals for: Pancreas (single agent – 1996) NSCLC (combination with cisplatin – 1998) Metastatic Breast Cancer (combination with paclitaxel – 2004) Gemzar plus carboplatin (GCb) combinations are used extensively in lung, breast, and bladder cancers Gemzar as a single agent, and in combination with carboplatin, has been extensively studied in ovarian cancer Safety profile well-characterized with relatively low toxicity

    8. 8 Objectives of Presentation

    9. 9 Management of Ovarian Cancer Robert Ozols, MD, PhD Sr. Vice President Medical Science Fox Chase Cancer Center

    10. 10 Ovarian Cancer – Current Clinical Practice

    11. 11 Chemotherapy for Platinum-Resistant Disease

    12. 12 Efficacy Results of Select Single-Agent Chemotherapies in Ovarian Cancer Efficacy results from registration trials for approved agents in recurrent ovarian cancer, according to their package insertEfficacy results from registration trials for approved agents in recurrent ovarian cancer, according to their package insert

    13. 13 Gemzar Monotherapy: Recurrent Ovarian Cancer Gemzar monotherapy efficacy results in platinum-resistant disease are comparable to already approved agents Less toxic regimen, very few transfusionsGemzar monotherapy efficacy results in platinum-resistant disease are comparable to already approved agents Less toxic regimen, very few transfusions

    14. 14 Chemotherapy for Platinum-Sensitive Disease and Combination Therapy

    15. 15 AGO-OVAR Development of Gemzar

    16. 16 PFS for Evaluation of Ovarian Cancer Agents

    17. 17 Clinical Efficacy Pivotal Study JHQJ / OVAR 2.5 Allen Melemed, MD Associate Medical Director, Eli Lilly and Co.

    18. 18 GCb Submission for Recurrent Ovarian Cancer

    19. 19 Study Design for JHQJ / OVAR 2.5

    20. 20 Key Trial Features: Study Endpoints Randomized Phase 3 study AGO, NCIC-CTG, EORTC 12 countries, 105 investigators Primary Endpoint: PFS Time from randomization to progressive disease (PD) or death Patients who were alive without PD were censored at last visit 85% power to detect 41% improvement in PFS (HR=0.71) at ?=0.05 (requiring ~300 events) Secondary Endpoints: Overall survival Response rate PRO (measured by EORTC QLQ-C30, OV28 instruments) Toxicity

    21. 21 Methodology for Disease Assessment for Study JHQJ / OVAR 2.5

    22. 22 Patient Characteristics for JHQJ / OVAR 2.5

    23. 23 JHQJ / OVAR 2.5 Primary Endpoint: Progression-Free Survival

    24. 24 JHQJ / OVAR 2.5 Efficacy Results: Overall Survival

    25. 25 JHQJ / OVAR 2.5 Post-Discontinuation Therapy

    26. 26 JHQJ / OVAR 2.5: Overall Response Rate

    27. 27 Efficacy Conclusions

    28. 28 Safety Results and Patient Benefit Pivotal Study JHQJ / OVAR 2.5 Richard Gralla, MD Multinational Association of Supportive Care in Cancer

    29. 29 Objectives Patient safety Toxicities and adverse events Significant consequences Translating PFS improvement to patient benefit Patient reported outcomes Time off chemotherapy

    30. 30 JHQJ / OVAR 2.5: Selected Grade 3/4 Toxicities Regardless of Causality

    31. 31 JHQJ / OVAR 2.5: Maximum CTC Neurotoxicity in Patients with Pre-Existing Neuropathy at Baseline

    32. 32 JHQJ / OVAR 2.5: Overview of Adverse Events

    33. 33 JHQJ / OVAR 2.5: Selected Grade 3/4 Non-Laboratory Toxicities Regardless of Causality

    34. 34 JHQJ / OVAR 2.5: Overview of Hospitalizations and Deaths

    35. 35 JHQJ / OVAR 2.5 Safety Conclusions

    36. 36 Patient Benefit Patient reported outcomes EORTC QLQ-C30 cancer specific instrument (validated – Aaronson, 1993 and Groenvold, 1997) EORTC QLQ-OV28 ovarian specific instrument (validated – Cull, 2001 and Greimel, 2003) AUC Analysis to 10-Point Change Time off chemotherapy Duration of time patients were off chemotherapy

    37. 37 JHQJ / OVAR 2.5: Patient Reported Outcome Assessment Methodology Total of 22 symptom scales included in the EORTC QLQ-OV28 and EORTC QLQ-C30 Symptoms most relevant to ovarian patients Nausea/vomiting Constipation Diarrhea Abdominal / GI (i.e. bloating) Fatigue Pain Anorexia Study designed to treat patients for 6 cycles or to progression Compliance rate completing PRO instrument ~90%

    38. 38 JHQJ / OVAR 2.5: Percent of Patients with Symptoms* at Baseline

    39. 39 JHQJ / OVAR 2.5: AUC Results for QoL Scales/Items Relevant to Ovarian Cancer

    40. 40 JHQJ / OVAR 2.5 - Global Quality of Life: 10-Point Changes (% Improved and Time to Worsening)

    41. 41 Patient Benefit Patient reported outcomes EORTC QLQ-C30 cancer specific instrument (validated – Aaronson, 1993 and Groenvold, 1997) EORTC QLQ-OV28 ovarian specific instrument (validated – Cull, 2001 and Greimel, 2003) AUC Analysis to 10-Point Change Time Off Chemotherapy Duration of time patients were off chemotherapy

    42. 42 JHQJ / OVAR 2.5: Time Off Chemotherapy

    43. 43 JHQJ / OVAR 2.5: Patient Benefit Conclusions

    44. 44 Robustness of JHQJ / OVAR 2.5 Efficacy Results Daniel J Sargent, PhD Director, Cancer Center Statistics Mayo Clinic, Rochester

    45. 45 Objectives

    46. 46 Robustness of PFS Results in Study JHQJ / OVAR 2.5

    47. 47 JHQJ / OVAR 2.5: Sensitivity Analysis Including Only Objective Progressions (SA1)

    48. 48 JHQJ / OVAR 2.5: Sensitivity Analysis Including Only Documented Objective Progressions (SA3)

    49. 49 JHQJ / OVAR 2.5: Summary of New Sensitivity Analyses for PFS

    50. 50 JHQJ / OVAR 2.5: Internal Consistency of PFS in Subgroups

    51. 51 JHQJ / OVAR 2.5: Independent Assessment of Response Rate

    52. 52 JHQJ / OVAR 2.5: Response in Independently Reviewed Cohort (Investigator vs Independent)

    53. 53 JHQJ / OVAR 2.5: Response Rate in Independently Reviewed Cohort

    54. 54 Conclusions

    55. 55 Concluding Remarks Benefit-Risk Summary: OVAR 2.5 in Context Tate Thigpen, MD Professor of Medicine, University of Mississippi School of Medicine

    56. 56 PFS is an Appropriate Measure of Treatment Activity in Ovarian Cancer

    57. 57 Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference- 2004

    58. 58 PFS is an Appropriate Measure of Treatment Activity in Ovarian Cancer

    59. 59 JHQJ / OVAR 2.5 Efficacy Results

    60. 60 Impact of Subsequent Chemotherapy on Survival for Recurrent Ovarian Cancer Subsequent therapy for ovarian cancer may impact survival results Cisplatin vs paclitaxel vs paclitaxel/cisplatin Dox/Cyclo vs Cis/Dox/Cyclo Frequency of subsequent therapy in studies of platinum-sensitive recurrent ovarian cancer ICON 4 (3rd line therapy not reported) Standard practice in UK would be no 3rd-line therapy JHQJ / OVAR 2.5 (75% patients received 3rd-line therapy)

    61. 61 Advancing the Treatment of Recurrent Ovarian Cancer

    62. 62 GCb is a Valuable Treatment Option for Patients with Recurrent Ovarian Cancer

    63. Back ups presented

    64. 64 JHQJ / OVAR 2.5: Pre- and Post-Discontinuation Assessment Intervals

    65. 65 JHQJ / OVAR 2.5: Clinical versus Objective Progressions

    66. 66 JHQJ / OVAR 2.5: Measurement Methods at Baseline

    67. 67 JHQJ / OVAR 2.5: EORTC QLQ-C30 Within Arm Changes Over Time

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