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 8001.01

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 Richard Gaynor, MD Vice President, Oncology Lilly Research Laboratories Robert Ozols, MD, PhD Sr. Vice President Medical Science, Fox Chase Cancer Center Allen Melemed, MD Associate Medical Director, Oncology – Eli Lilly and Co. Richard Gralla, MD Multinational Association of Supportive Care in Cancer Daniel Sargent, PhD Director, Cancer Center Statistics, Mayo Clinic Tate Thigpen, MD Professor of Medicine, University of Mississippi School of Medicine 8002.01

Expert Participants Eli Lilly and Company External Consultants 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 External Consultants Richard Gralla, MD Multinational Association of Supportive Care in Cancer Robert Ozols, MD, PhD Sr. Vice President Medical Science, Fox Chase Cancer Center Jacobus Pfisterer, MD, PhD Universitätsklinikum Schleswig-Holstein, Campus Kiel, Germany, AGO co-Chair, GCIG Chair Dan Sargent, PhD Director, Cancer Center Statistics, Mayo Clinic, Rochester Tate Thigpen, MD Professor of Medicine, University of Mississippi School of Medicine 8003.01

Ovarian Cancer Supplemental NDA sNDA for ovarian cancer indication was submitted 16 June 2005 Submission based on a 356 patient randomized Phase 3 study conducted by AGO-OVAR that met its primary endpoint of statistically significant improvement in progression free survival (PFS) Indication Gemzar in combination with carboplatin for the treatment of women with recurrent ovarian cancer that have relapsed at least 6 mo following platinum‑based therapy. Dosage Gemzar 1000 mg/m2 days 1 and 8 Carboplatin AUC 4 day 1 8004.01

Gemzar sNDA Ovarian Cancer Oncolytic agents are often used off-label Gemzar alone and in combination with carboplatin listed in NCCN 2006 practice guidelines for treatment of women with recurrent ovarian cancer and is currently used in the treatment of this disease “FDA Guidance on New Treatment Indications” goals: Submission of data for supplemental indications Label all indications where data exists to establish safety and efficacy Recognize alternative data sources from cancer clinical trial organizations with track record of high quality research Current study performed by a well-known European cooperative group is consistent with FDA guidance and demonstrates the efficacy of GCb in recurrent ovarian cancer 8005.01

Regulatory Background Historically, overall response rate has been primarily used for approval in recurrent ovarian cancer Lilly requested meeting with FDA to discuss potential for submission (December 2004) FDA agreed data package met criteria for submission PFS endpoint, used in this trial, is acknowledged as a measure of clinical benefit in lung and colorectal cancers Lilly will discuss that the totality of data including PFS, ORR, PRO and time off chemotherapy supports full approval of Gemzar /carboplatin for treatment of women 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. 8006.01

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 8007.01

Objectives of Presentation Gemzar is active in ovarian cancer Gemzar plus carboplatin provides a clinical benefit for women with recurrent ovarian cancer Superior PFS, overall and complete response rates Robust and internally consistent efficacy Improved patient reported outcomes and time off chemotherapy Safe and well-tolerated regimen No new safety issues Low incidence of neurotoxicity Gemzar plus carboplatin is an effective, less neurotoxic treatment option for women with recurrent ovarian cancer 8008.01

Management of Ovarian Cancer Robert Ozols, MD, PhD Sr. Vice President Medical Science Fox Chase Cancer Center 8009.01

Ovarian Cancer – Current Clinical Practice 20,180 new cases and 15,310 deaths estimated in 2006 Current standard therapy for initial treatment: Debulking surgery followed by Cb + paclitaxel After 1st-line treatment with Cb + paclitaxel therapy for advanced stage disease: 75% of patients will achieve a complete clinical remission Of those, 75% will ultimately relapse Median disease-free interval of < 2 years Median survival after relapse is 18-24 mo Neuropathy is a significant issue following initial therapy 75% - 80% have grade 1-4 neurotoxicity 30% of patients with > grade 2 neurosensory toxicity 7% of patients with > grade 2 neuromotor toxicity 8010.01

Chemotherapy for Platinum-Resistant Disease Selection of chemotherapy dependent on: Platinum-free interval at time of relapse Platinum resistant Platinum sensitive Residual toxicity, performance status, co-morbid conditions Platinum resistant: <6 mo interval between treatment and PD Current treatment options Liposomal doxorubicin* Topotecan* Paclitaxel* Gemzar Response rates for platinum-resistant patients ~10% Time to progression for platinum-resistant patients ~3 mo * FDA-approved agent 8011.01

Efficacy Results of Select Single-Agent Chemotherapies in Ovarian Cancer Liposomal doxorubicin Topotecan Paclitaxel Patient Population Recurrent / Platinum-resistant Recurrent / Platinum – resistant Recurrent N (Number and phase of studies) 384 (3 Ph 2, 1 Ph 3) 223 (1 Ph 2, 1 Ph 3) 499 (2 Ph 2, 1 Ph 3) ORR, % 0 – 22* 14 – 21 13 – 22 Median TtPD, mo 3.7** 2.6 – 4.4 2.8 – 4.4 Efficacy results from registration trials for approved agents in recurrent ovarian cancer, according to their package insert * Does not include an outlier study in which no responders were reported ** Combined data from all three studies 8499.01

Gemzar Monotherapy: Recurrent Ovarian Cancer Lund Friedlander Von Minckwitz Patient Population Platinum- resistant Recurrent N 42 36 ORR, % 19 14 22 CR, % 6 5 Median TtPD, mo 2.8 3.0 3.6 Gemzar monotherapy efficacy results in platinum-resistant disease are comparable to already approved agents Less toxic regimen, very few transfusions 8013.01

Chemotherapy for Platinum-Sensitive Disease and Combination Therapy Platinum sensitive:  6 mo interval between treatment and PD Current treatment options based on Cb therapy Single Agent* Combination with Gemzar, paclitaxel ICON 4 Important proof-of-concept for use of combination Improved OS and PFS Toxicities limit utility High percent of neurotoxicity (>Gr. 2 = 20%) Only 45% patients received prior taxane in ICON 4 Neurotoxicity may be higher in US due to standard of care in 1st line (Carbo plus paclitaxel) * FDA-approved agent 8498.01

AGO-OVAR Development of Gemzar Effective, less neurotoxic regimen needed in recurrent disease Gemzar and Cb both active agents AGO-OVAR Well-established European cooperative group specializing in gynecological malignancies Member of Gynecological Cancer Intergroup Organization of 15 international cooperative groups Participated in ICON 4 (OVAR 2.2), withdrew due to toxicity Evaluated safety and efficacy of GCb in Ph 1/2 (SO026) Observed low incidence of neurotoxicity Designed JHQJ / OVAR 2.5 GCb is effective regimen in treatment of recurrent disease 8014.01

PFS for Evaluation of Ovarian Cancer Agents Recognized as an important endpoint for 1st and 2nd line treatment of ovarian cancer patients, according to the Ovarian Cancer Consensus Conference Not confounded by post discontinuation therapies Survival may be confounded with multiple lines of therapy Represents efficacy of only study therapy Earlier identification of active treatments PFS in conjunction with other efficacy parameters (ORR, CR, QoL) can be a measure of clinical benefit in ovarian cancer AGO JHQJ / OVAR 2.5 met the primary endpoint of a statistically significant improvement in PFS 8018.01

Clinical Efficacy Pivotal Study JHQJ / OVAR 2.5 Allen Melemed, MD Associate Medical Director, Eli Lilly and Co. 8021.01

GCb Submission for Recurrent Ovarian Cancer Study ID Phase ORR (%) Median PFS (mo) Median Survival (mo) JHQJ / OVAR 2.5 Phase 3 47.2 8.6 18.0 OVAR 2.4 / O026 Phase 1-2 62.5 10.0 22.5 JHRW Phase 2 9.6 26.9 Additional Supportive Studies in ovarian cancer: Three Phase 2 studies using Gemzar + carboplatin Ten Phase 2 studies using Gemzar monotherapy 8022.01

Study Design for JHQJ / OVAR 2.5 R A N D O M I Z A T I O N Stratified at central AGO office by: Platinum-free interval (PFI) (6-12 or > 12 mo) Type of 1st-line platinum therapy (platinum-paclitaxel or other platinum therapy) Bidimensionally measurable disease (yes or no) Gemzar 1000 mg/m² D1+8 Carboplatin AUC 4 D1 q 3w for 6 cycles Carboplatin AUC 5 D1 q 3w for 6 cycles 8024.01

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 8025.01

Methodology for Disease Assessment for Study JHQJ / OVAR 2.5 Disease assessments every 6 weeks on-study Radiologic imaging studies (same method as baseline) Physical examination for tumor size Thirty days after study discontinuation (V101) disease assessments occurred every 3 mo Using the same method as baseline Determination of events for PFS: Death Objective tumor progression Clinical progression (performance status decline of 2 levels; progressive peritoneal carcinomatosis with increasing bowel dysfunction; increased ascites requiring palliative drainage) 8027.01

Patient Characteristics for JHQJ / OVAR 2.5 GCb (N=178) Cb (N=178) Mean age, years (range) 58.1 (36.0-78.0) 56.5 (21.0-81.0) ECOG PS, n (%) 0-1 162 (91.0) 165 (92.7) 2 11 (6.3) 9 (5.2) FIGO stage at initial diagnosis, n (%) Ia-IIIa 38 (21.3) 26 (14.6) IIIb-IIIc 113 (63.5) 129 (72.5) IV 27 (15.2) 22 (12.4) First-line therapy, n (%) Platinum 178 (100) Platinum and paclitaxel 122 (68.5) 120 (67.4) Platinum-free interval, n (%) 6-12 months 71 (39.9) >12 months 105 (59.0) 106 (59.6) 8030.01

JHQJ / OVAR 2.5 Primary Endpoint: Progression-Free Survival 3 6 9 12 15 18 21 24 27 30 33 36 39 0.0 0.2 0.4 0.6 0.8 1.0 Progression-Free Survival Time (mo) Progression-Free Probability Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) GCb: median = 8.6 mo Censoring: 12.4% GCb Arm (N=178) Cb Arm (N=178) Cb: median = 5.8 mo Censoring: 12.9% * Adjusted for PFI, Tumor size 8031.01

JHQJ / OVAR 2.5 Efficacy Results: Overall Survival Log-rank p-value = 0.8977 Unadjusted HR = 0.98 (0.78 to 1.24) Adjusted* HR = 0.92 (0.72 to 1.16) 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 6 12 18 60 54 48 42 36 30 24 GCb Arm (N=178) Cb Arm (N=178) Proportion Surviving Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Months * Adjusted for PFI, Tumor size and performance status 8032.01

JHQJ / OVAR 2.5 Post-Discontinuation Therapy Percent of Patients Post-discontinuation therapy GCb (N=178) Cb (N=178) Any post-discontinuation therapy 83.7 78.7 Chemotherapy 75.8 72.5 1 regimen 16.3 13.5 2 regimens 12.4 15.7 3 or more regimens 9.6 10.7 Unspecified number of regimens 37.6 32.6 Hormonal, immuno or biological therapy 19.7 18.0 Radiation 5.1 Other therapy – not specified 15.2 8033.01

JHQJ / OVAR 2.5: Overall Response Rate GCb Arm (N=178) Cb Arm (N=178) Chi-square p-value ORR (95% CI) 47.2% (39.9 - 54.5) 30.9% (24.1- 37.7) 0.0016 CR Rate (95% CI) 14.6% (9.4 to 19.8) 6.2% (2.6 to 9.7) 0.0092 8354.01

Efficacy Conclusions Well designed, Phase 3, co-operative group study Patient characteristics well-balanced Study population representative of a high-risk recurrent ovarian cancer patients High percent of prior taxane therapy Primary endpoint (PFS) is highly significant in favor of the combination arm 28% reduction in risk Overall and complete response rates are significantly improved in the GCb arm vs the Cb arm Gemzar plus carboplatin demonstrated clinically meaningful benefit for women with recurrent ovarian cancer 8054.01

Safety Results and Patient Benefit Pivotal Study JHQJ / OVAR 2.5 Richard Gralla, MD Multinational Association of Supportive Care in Cancer 8021.01

Objectives Patient safety Toxicities and adverse events Significant consequences Translating PFS improvement to patient benefit Patient reported outcomes Time off chemotherapy 8410.01

JHQJ / OVAR 2.5: Selected Grade 3/4 Toxicities Regardless of Causality Percent of Patients GCb Arm (N=175) Cb Arm (N=174) Grade 3 Grade 4 Hemoglobin 22.3* 5.7 8.6 2.3 Neutrophils 41.7* 28.6* 10.9 1.1 Platelets 30.3* 4.6 10.3 Nausea 6.3 2.9 Vomiting 0.6 Diarrhea 3.4 Constipation * p-value <0.01 8038.01

Max. Neuropathy On Study (%) JHQJ / OVAR 2.5: Maximum CTC Neurotoxicity in Patients with Pre-Existing Neuropathy at Baseline Max. Neuropathy On Study (%) Patients with neuropathy at baseline Gr 1 Gr 2 Gr 3 Gr 4 GCb Arm (N=38) Motor Neuropathy 2.6 Sensory Neuropathy 10.5 Cb Arm (N=29) 6.9 8040.01

JHQJ / OVAR 2.5: Overview of Adverse Events N (Percent of Patients) GCb Arm (N=175) Cb Arm (N=174) p-value Serious adverse events All 49 (28.0) 37 (21.3) 0.1718 Possibly related to study drug 29 (16.6) 17 (9.8) 0.0810 Discontinuations due to AEs 19 (10.9) 0.8606 14 (8.0) 1.0000 8037.01

JHQJ / OVAR 2.5: Selected Grade 3/4 Non-Laboratory Toxicities Regardless of Causality Percent of Patients GCb (N=175) Cb (N=174) Grade 3 Grade 4 Hemorrhage 1.8 0.6 1.1 Febrile neutropenia Neuropathy – sensory 2.3 Neuropathy – motor 8039.01

JHQJ / OVAR 2.5: Overview of Hospitalizations and Deaths N, (Percent of Patients GCb Arm (N=175) Cb Arm (N=174) p-value Patients hospitalized due to AE* All 44 (24.7) 32 (18.0) 0.1545 Possibly related to study drug 29 (16.3) 16 (9.0) 0.0547 Deaths On study (during treatment period) 4 (2.3) 3 (1.7) 1.0000 Within 30-day poststudy follow up 1 (0.6) 2 (1.1) 0.6228 * Based on all randomized patients, N=178 per arm 8429.01

JHQJ / OVAR 2.5 Safety Conclusions GCb is a safe and well-tolerated regimen No new safety issues emerge in JHQJ / OVAR 2.5 Certain hematologic Gr 3/4 toxicities increased in GCb arm Clinically significant sequelae occurred at low and comparable rates Low incidence of neurotoxicity Gemzar plus carboplatin is a safe regimen for treatment of women with recurrent ovarian cancer. 8041.01

Patient Benefit Patient reported outcomes Time off chemotherapy 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 8430.01

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% 8434.01

JHQJ / OVAR 2.5: Percent of Patients with Symptoms* at Baseline GCb Arm >4 Cb Arm 3 Number of Symptoms 2 Most Frequent Symptoms: Fatigue 86% Abdominal symptoms 84% Pain 71% 1 10 20 30 40 50 60 Percent of Patients * Nausea/vomiting, constipation, diarrhea, abdominal GI symptoms, fatigue, pain, or anorexia 8436.01

Overall improvements in the GCb arm in 21 of 22 scales JHQJ / OVAR 2.5: AUC Results for QoL Scales/Items Relevant to Ovarian Cancer GCb Arm 80 Cb Arm 70 60 50 Percent of Maximum AUC 40 30 20 10 Global QoL N/V Constipation Diarrhea Abd/ GI Fatigue Pain Anorexia Symptom Overall improvements in the GCb arm in 21 of 22 scales Sign test <0.0001 8137.01

JHQJ / OVAR 2.5 - Global Quality of Life: 10-Point Changes (% Improved and Time to Worsening) GCb Arm 70 Cb Arm 60 Probability 1.0 0.8 0.6 0.4 0.2 0.0 6 12 3 9 Time to > 10 Point Worsening in Global QoL (mo) HR (95% CI): 0.75 (0.54 – 1.04) Log-rank p-value: 0.084 GCb median=6.2 months; 61.2% censoring Cb median=4.3 months; 57.9% censoring 50 40 30 Percent of Patients 20 10 Global QoL Percent of Patients Improved by at Least 10 Points (p = 0.106) 8438.01

Patient Benefit Patient reported outcomes Time Off Chemotherapy 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 8430.01

JHQJ / OVAR 2.5: Time Off Chemotherapy 1.0 0.9 0.8 0.7 HR (95% CI): 0.80 (0.64 – 0.99) Log-rank p-value: 0.0417 0.6 Probability 0.5 GCb median=5.6 months; e=169; 5.1% censoring 0.4 Cb median=2.6 months; e=165; 7.3% censoring 0.3 0.2 0.1 0.0 0.0 6 12 18 24 30 36 42 Months 8433.01

JHQJ / OVAR 2.5: Patient Benefit Conclusions The GCb regimen is safe with an acceptable toxicity profile Quality of life and patient reported outcome differences between the arms consistently favor the GCb regimen Women on the GCb regimen experienced a significantly greater time off chemotherapy following study therapy Gemzar plus carboplatin shows improved patient benefit with low toxicity and longer time off chemotherapy. 8041.01

Robustness of JHQJ / OVAR 2.5 Efficacy Results Daniel J Sargent, PhD Director, Cancer Center Statistics Mayo Clinic, Rochester 8042.01

Objectives Confirm robustness of the primary endpoint PFS Sensitivity analyses Consistency of results in key subgroups Assess possible impact of investigator bias PFS Response rate Investigator vs independent assessments 8043.01

Robustness of PFS Results in Study JHQJ / OVAR 2.5 Sensitivity analysis including only objective progressions (SA1) Clinical progressions ignored Sensitivity analysis including only documented objective progressions (SA3) Objective progressions without lesion measurements ignored Objective progressions following missed / incomplete assessments back-dated Interval trimmed at 7 mo or at study discontinuation (V101) 8366.01

JHQJ / OVAR 2.5: Sensitivity Analysis Including Only Objective Progressions (SA1) HR (95% CI): 0.76 (0.60 – 0.95) Log-rank p-value: 0.0157 1.0 GCb: Median: 9.7 mo ; events=148; Cens: 16.9% 0.8 Cb: Median: 6.7 mo ; events=149; Cens: 16.3% 0.6 Progression Free Probability GCb Arm Cb Arm 0.4 0.2 0.0 6 12 18 24 30 36 Progression Free Survival Time (Months) 8363.01

HR (95% CI): 0.45 (0.32 – 0.64) Log-rank p-value: <0.0001 JHQJ / OVAR 2.5: Sensitivity Analysis Including Only Documented Objective Progressions (SA3) HR (95% CI): 0.45 (0.32 – 0.64) Log-rank p-value: <0.0001 0.0 0.2 0.4 0.6 0.8 1.0 Progression Free Probability 2 4 6 8 10 Progression Free Survival Time (mo) GCb Median : 6.7 mo Events=47 Cens: 73.6% Cb Median: 5.2 mo Events=84 Cens: 52.8% GCb Arm Cb Arm 8365.01

JHQJ / OVAR 2.5: Summary of New Sensitivity Analyses for PFS Median GCb (censoring) Median Cb (censoring) LR p-value HR Primary PFS 8.6 mo (12.4%) 5.8 mo (12.9%) 0.0038 0.72 Sensitivity Analysis Including Only Objective Progressions (SA1) 9.7 mo (16.9%) 6.7 mo (16.3%) 0.0157 0.76 Sensitivity Analysis Including Only Documented Objective Progressions (SA3) 6.7 mo (73.6%) 5.2 mo (52.8%) <0.0001 0.45 8362.01

JHQJ / OVAR 2.5: Internal Consistency of PFS in Subgroups HR (95% CI) Interaction p-value Age <60 y 0.74 (0.54-1.01) 0.8552 >60 y 0.70 (0.51-0.97) Performance status 0.69 (0.50-0.95) 0.7392 1 or 2 0.73 (0.53-1.01) Platinum-free 6-12 mo 0.69 (0.49-0.98) 0.7500 interval >12 mo 0.72 (0.54-0.97) 1st Line paclitaxel Yes 0.61 (0.47-0.80) 0.0704 No 0.91 (0.61-1.36) Median tumor area <18.7 0.84 (0.60-1.17) 0.1636 (cm2) >18.7 0.60 (0.43-0.83) 8049.01

JHQJ / OVAR 2.5: Independent Assessment of Response Rate Process for independent review: All imaging films submitted by the investigator were given to the review board Patients needed to have a baseline and one subsequent radiologic image Ultrasound and physical exam data were not included in the review Members of the review board (3 outside radiologists) were blinded to the treatment arm, investigator assessment and target lesions Independent assessment was performed on the subset of 222 patients with radiologic imaging available Reduced power 8035.01

JHQJ / OVAR 2.5: Response in Independently Reviewed Cohort (Investigator vs Independent) Independent Review Investigator Assessment Responders Non-Responders 66 25 (11%) 26 (12%) 105 8053.01

JHQJ / OVAR 2.5: Response Rate in Independently Reviewed Cohort Investigator Assessed GCb, (N=121) Response Rate 46.3% CR/PR 11/45 15/41 Cb, (N=101) 35.6% 34.7% 4/32 4/31 p-value 0.1091 0.0794 8052.01

Conclusions Primary endpoint (PFS) is statistically convincing and internally consistent Multiple sensitivity analyses confirm robustness of primary analysis Significant benefit reproduced in key patient subgroups No evidence of investigator bias Results from independent review of response consistent with investigator assessment Concordance analysis showed no bias Similar overall response rates among independent and investigator assessments 8054.01

Concluding Remarks Benefit-Risk Summary: OVAR 2.5 in Context Tate Thigpen, MD Professor of Medicine, University of Mississippi School of Medicine 8055.01

PFS is an Appropriate Measure of Treatment Activity in Ovarian Cancer Recognized as an important endpoint for 1st and 2nd line treatment of ovarian cancer patients, according to the Ovarian Cancer Consensus Conference AGO-OVAR was the host for the 2004 meeting Not confounded by post discontinuation therapies Survival may be confounded with multiple lines of therapy Represents efficacy of only study therapy PFS differences can alter treatment practices PFS in conjunction with other efficacy parameters can be a measure of clinical benefit in ovarian cancer 8018.01

Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference- 2004 8514.01

PFS is an Appropriate Measure of Treatment Activity in Ovarian Cancer Recognized as an important endpoint for 1st and 2nd line treatment of ovarian cancer patients, according to the Ovarian Cancer Consensus Conference AGO-OVAR was the host for the 2004 meeting Not confounded by post discontinuation therapies Survival may be confounded with multiple lines of therapy Represents efficacy of only study therapy PFS differences can alter treatment practices PFS in conjunction with other efficacy parameters can be a measure of clinical benefit in ovarian cancer 8018.01

JHQJ / OVAR 2.5 Efficacy Results JHQJ / OVAR 2.5 (N=356) Efficacy Results PFS (primary endpoint) 8.6 mo vs 5.8 mo HR = 0.72 (p=0.0038) ORR 47.2% vs 30.9% p-value = 0.0016 CR 14.6% vs 6.2% p-value = 0.0092 Patient Reported Outcomes Consistent trend for improvement 8058.01

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) 8497.01

Advancing the Treatment of Recurrent Ovarian Cancer Standard of care in front-line ovarian cancer is Cb plus paclitaxel Neurotoxicity is a frequent complication of this treatment Standard of care in recurrent platinum-sensitive ovarian cancer is platinum-based therapy Combination therapy has shown improvements in efficacy over single agent Cb in recurrent ovarian cancer Effective, less neurotoxic regimen is needed 8065.01

GCb is a Valuable Treatment Option for Patients with Recurrent Ovarian Cancer Gemzar plus carboplatin showed an advantage over carboplatin Clinically meaningful improvements in PFS that were robust, internally consistent, and statistically significant Significantly greater overall and complete response rates Manageable and well-characterized safety profile Infrequent neurotoxicity and alopecia Longer period without a decline in QoL Longer time without need for further chemotherapy JHQJ / OVAR 2.5 is a positive study with regard to its primary endpoint, PFS, and supporting endpoints Gemzar plus carboplatin is an effective treatment option for women with recurrent ovarian cancer. 8066.01

Back ups presented

JHQJ / OVAR 2.5: Pre- and Post-Discontinuation Assessment Intervals Weeks On-Treatment* Off-Treatment** Summary Statistics GCb (N=168) Cb (N=159) GCb (N=117) Cb (N=80) 25th Percentile 5.4 5.0 4.6 4.4 Median 6.3 6.1 8.3 75th Percentile 7.7 7.6 10.0 10.5 * Intervals between disease assessment dates ** Intervals between office visit dates 8384.01

JHQJ / OVAR 2.5: Clinical versus Objective Progressions N (Percent of Patients) On-Treatment Off-Treatment Progressive Disease GCb (N=35) Cb (N=70) GCb (N=117)* Cb (N=80)** Clinical Progression 1 (3) 7 (10) 28 (24) 16 (20) Objective Progression 34 (97) 63 (90) 92 (79) 66 (82.5) Three patients were counted twice, all 3 patients had both larger/new lesions and deteriorating conditions as the basis of PD ** Two patients were counted twice, both patients had larger/new lesions and deteriorating conditions as the basis of PD 8050.01

JHQJ / OVAR 2.5: Measurement Methods at Baseline Number of Patients (%) Method GCb (N=178) Cb (N=178) CT-Scan 126 (71) 110 (62) Ultra Sound 39 (22) 51 (29) Physical Exam 14 (8) 21 (12) MRI 5 (3) 6 (3) Chest X-ray 1 (0.6) Gynecological Exam 8321.01

JHQJ / OVAR 2.5: EORTC QLQ-C30 Within Arm Changes Over Time GCb Arm (N=154) Cb Arm (N=152) Global QoL Improved Stable Physical functioning Role functioning Cognitive functioning Emotional functioning Social functioning Fatigue Nausea/vomiting Worsened Pain Dyspnea Sleep disturbance Appetite loss Constipation Diarrhea Financial impact 8387.01