CC39/11-1 ZOMETA ® in Prostate Cancer and Solid Tumors Other Than Prostate Cancer and Breast Cancer: Placebo-Controlled Trials Matthew Smith, MD, PhD Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Prof. Robert Coleman, MD, FRCP Cancer Research Centre Weston Park Hospital Sheffield, England C

CC39/11-2 Placebo-Controlled Trials Study Objective  Demonstrate that ZOMETA ® is superior to placebo for the treatment of bone metastases C

CC39/11-3 Placebo-Controlled Trials Study Endpoints (1)  Primary endpoint – Proportion (%) of patients experiencing any skeletal-related event (SRE) not including hypercalcemia of malignancy (HCM) C

CC39/11-4 Placebo-Controlled Trials Study Endpoints (2)  Secondary endpoints – Time to first SRE – Skeletal morbidity rate (SMR) – Andersen-Gill multiple event analysis – Time to first SRE, SMR, and proportion (%) of patients with any SRE (+HCM) – Pain/analgesic scores – Bone lesion response – Time to progression of disease – Safety (including survival) Additional 6 mo of survival and serum creatinine data C

CC39/11-5 Placebo-Controlled Trials Skeletal-Related Events (SREs)  Pathologic fractures  Spinal cord compression  Radiation for bone pain or to treat or prevent pathologic fractures or spinal cord compression  Surgery to bone  Change of antineoplastic therapy for bone pain in prostate cancer  Hypercalcemia of malignancy (HCM) C

CC39/11-6 Placebo-Controlled Trials Preplanned SRE Analysis  Proportion (%) of patients with an SRE – Number of patients with SRE divided by number of patients in each treatment group  Time to first SRE – Time from randomization to first SRE (days)  Skeletal morbidity rate (SMR) § – Number of SREs divided by time at risk on trial (yr)  Andersen-Gill multiple event analysis – Time from randomization to each occurrence of the events § C §Skeletal events occurring within 21 days counted as a single occurrence.

CC39/11-7 Clinical Trials History  Original study design – ZOMETA ® (8 mg or 4 mg) versus placebo infused over 5 min every 3 wk for 9 (–PC/BC) or 15 mo (prostate cancer)  Renal amendment 1 (June 1999) – Infusion time for ZOMETA increased from 5 min to 15 min – Infusion volume increased from 50 mL to 100 mL  Renal amendment 2 (June 2000) – 8 mg switched to 4 mg (8/4-mg group) – Renal function monitoring within 2 wk prior to each dose  Statistical amendment – Primary efficacy analysis based on ZOMETA 4 mg versus placebo C

CC39/11-8 Clinical Trial History Amendment/Patient Accrual Timeline 29 6/9812/986/996/0012/0012/99 Accrual 1/01 Treatment and follow-up Prostate cancer N = N = 773 Solid tumors –PB/BC Renal amendment 1 (5  15 min Infusion) Renal amendment 2 (8 mg  4 mg Dose)

CC39/11-9 ZOMETA ® in Prostate Cancer: Placebo-Controlled Trial (039) C

CC39/11-10 Prostate Cancer Trial Design (1)  Prostate carcinoma – Documented bone metastases  Rising PSA  Baseline serum testosterone within the castrate range (  50 ng/dL)  No strong opiate analgesics  Serum creatinine  3.0 mg/dL (265 µmol/L)  ECOG performance status 0, 1, 2  Appropriate antineoplastic therapy at study entry C

CC39/11-11 Prostate Cancer Trial Design (2)  Stratification – Presence or absence of any distant metastases at initial diagnosis of cancer  Patients received oral vitamin D 400 IU and calcium 500 mg  Dose and dosing regimen – ZOMETA ® 4 mg, 8/4 mg, and placebo – 5-min amended to 15-min infusion – Every 3 wk  15-mo follow-up C

CC39/11-12 Prostate Cancer Demographics and Prognostic Factors ZOMETA ® ZOMETA 4 mg8/4 mg Placebo Demographic factorN = 214N = 221N = 208 Mean age, yr Gender, % male Race, Caucasian,% Black, % Performance status ECOG 0 - 1, % Mean FACT-G score No metastases at diagnosis, n Metastases at diagnosis, n Baseline PSA, median

CC39/11-13 Prostate Cancer Patient Disposition ZOMETA ® ZOMETA Disposition4 mg8/4 mg Placebo 8 ISE T2-3, 4 Intent-to-treat, N Completed study therapy (15 mo) n %

CC39/11-14 Prostate Cancer Reasons for Early Discontinuation Patients, % ZOMETA ® ZOMETA 4 mg8/4 mg Placebo Reason for discontinuationN = 214N = 221N = ISE T2-3, 4 Total discontinued prematurely Death Adverse events Withdrew consent Unsatisfactory therapeutic effect Protocol violation Lost to follow-up Other

CC39/11-15 Prostate Cancer Proportion (%) of Patients With an SRE Percent of patients N = P =.021 P =.222 ZOMETA 4 mg versus placebo remained significant when fractures were excluded

CC39/11-16 Why Was No Dose Effect Observed? Percent Change From Baseline N-telopeptide (039)  Maximum target inhibition was achieved in the ZOMETA 4 mg group CSR 039 T

CC39/11-17 Prostate Cancer Combined Analysis Proportion (%) of Patients With an SRE Percent of patients N = P =.041

CC39/11-18 Prostate Cancer Components of SRE by Month 15 8 ISE T 2-15;CSR 039 T9-4 N

CC39/11-19 Prostate Cancer Time to First SRE 011 PTF 9.2-1p3; CSR 039 T9-2: CSR 011 T9-3 ZOMETA 4 mg ZOMETA 8/4 mg Placebo Median time, daysP-value ZOMETA ® 4 mgNR.011 ZOMETA 8/4 mg Placebo321

CC39/11-20 Prostate Cancer Mean SMR* ZOMETA 8/4 mgZOMETA® 4 mgPlacebo N = P =.143 P =.006 * +HCM P <.05 for ZOMETA 4 mg versus placebo C

CC39/11-21 Prostate Cancer Andersen-Gill Multiple Event Analysis Time to SRE up to Month 15 ZOMETA ® 4 mg ZOMETA 8/4 mg Hazard95% CI forHazard95% CI for ratiohazard ratioratiohazard ratio Placebo0.643(0.476, 0.870)0.847(0.640, 1.122)

CC39/11-22 Prostate Cancer (039) Proportion of Patients With an SRE in Patients With Different Types of Bone Lesions 57 N =

CC39/11-23 Prostate Cancer Disease-Related Endpoints Median time, days ZOMETA ® ZOMETA P-value, 4 mg 8/4 mg Placebo ZOMETA 4 mg EndpointN = 214N = 221N = 208 vs placebo Time to progression of bone lesion, days Time to progression of disease, days C

CC39/11-24 Prostate Cancer Quality-of-Life Endpoints Change from baseline, mean  SD ZOMETA ® ZOMETA 4 mg 8/4 mg Placebo Endpoint (15 mo) N = 214N = 221 N = 208 Brief pain inventory score § 0.6    2.23 Analgesic score § 1.0    1.49 Performance status (ECOG) § 0.9    1.28 FACT-G total score || –7.4  17.7–7.4  15.4 –8.3  17.4 §Increased score = decline. ||Increased score = improvement. C

CC39/11-25 Prostate Cancer Efficacy Summary  ZOMETA decreases skeletal complications in men with prostate cancer and bone metastases C Time to Multiple Proportionfirst SREMean skeletalevent analysis with SRE, %(hazard ratio) morbidity ratehazard ratio ZOMETA ® 4 mg N = 214 P-value ZOMETA 8/4 mg N = 221 P-value Placebo N = 208— —

CC39/11-26 ZOMETA ® in Prostate Cancer: Placebo-Controlled Trial (039) Safety C

CC39/11-27 Primary Cause of Death During the Trial or Within 28 Days After Study Drug Termination § Patients, n (%) ZOMETA ® ZOMETA 4 mg8/4 mgPlacebo Cause of deathN = 214N = 218N = Neoplasms benign/ malignant 15(7.0)18(8.3)14(6.7) Respiratory/thoracic/ mediastinal3(1.4)2(0.9)5(2.4) Cardiac5(2.3)5(2.3)8(3.8) General disorders/ administration site 5(2.3)1(0.5)2(1.0) Infections/infestations2(0.9)2(0.9)4(1.9) Renal/urinary0(0.0)4(1.8)0(0.0) ISS T5-12 §6 mo additional data.

CC39/11-28 Prostate Cancer Survival – All Patients § ZOMETA 4 mg ZOMETA 8/4 mg Placebo Median time, days ZOMETA ® 4 mg 563P =.087 ZOMETA 8/4 mg418P =.765 Placebo E PTF p3 35 §6 mo additional data.

CC39/11-29 Safety-evaluable patients, n (%) ZOMETA ® 4 mg ZOMETA 8/4 mgPlacebo Preferred termN = 214N = 218N = 208 Bone pain108 (50.5) 133 (61.0)127 (61.1) Nausea 77 (36.0) 115 (52.8) 77 (37.0) Constipation 72 (33.6) 85 (39.0) 72 (34.6) Fatigue 70 (32.7) 67 (37.0) 53 (25.5) Anemia NOS 57 (26.6) 60 (27.5) 37 (17.8) Myalgia 53 (24.8) 53 (24.3) 37 (17.8) Vomiting NOS 46 (21.5) 64 (29.4) 43 (20.7) Weakness 45 (21.0) 50 (22.9) 40 (19.2) Anorexia 43 (20.1) 55 (25.2) 36 (17.3) Pyrexia 43 (20.1) 48 (22.0) 27 (13.0) Edema lower limb 41 (19.2) 48 (22.0) 27 (13.0) Dizziness (except vertigo) 38 (17.8) 22 (10.1) 24 (11.5) Diarrhea NOS 36 (16.8) 35 (16.1) 32 (15.4) Weight decreased 36 (16.8) 38 (17.4) 26 (12.5) Prostate Cancer Incidence of Adverse Events (  15%) Regardless of Study Drug Relationship NOS = Not otherwise specified. CSR 039 T10-2 C

CC39/11-30 Prostate Cancer NCI Grade 3/4 Hematology Electrolyte and Mineral Changes  Anemia – Incidence < 10% for all treatment groups with a higher incidence in the ZOMETA ® 8/4-mg treatment group – Higher use of red blood cells and erythropoietin in the ZOMETA treatment groups  Electrolyte and mineral adverse events – Incidence of hypocalcemia < 2% for all treatment groups – Higher incidence of hypophosphatemia and hypermagnesemia in the ZOMETA treatment groups 8 Vol 166 ISS PTT 5.1-5

CC39/11-31 Patients Enrolling After the 15-min Amendment NCI Grade 3/4 Serum Creatinine Changes § Patients, n (%) N = 257 ZOMETA ® ZOMETA 4 mg 8/4 mg Placebo N = 92 N = 87N = 78 Grade 3 5 (5.4)2 (2.3)1 (1.3) Grade 4 0 (0.0) 0 (0.0) 0 (0.0) C §6 mo additional data.

CC39/11-32 Prostate Cancer Kaplan-Meier Estimates of First Serum Creatinine Increase § n Hazard ratioP-value ZOMETA ® 4 mg ZOMETA 8/4 mg || Placebo E1 PTF p1 35 n Hazard ratioP-value ZOMETA 4 mg ZOMETA 8/4 mg ¶ Placebo78 §6 mo additional data. ||53% of patients received only 8 mg. ¶23% of patients received only 8 mg. Percent of patients without increase (randomized prior to 15-min infusion amendment) Percent of patients without increase (randomized after 15-min infusion amendment)

CC39/11-33 Prostate Cancer Safety Summary  Adverse events commonly associated with bisphosphonates (fever, myalgias, anemias, hypophosphatemia, hypermagnesemia) were reported more frequently in the ZOMETA ® treatment groups than in the placebo group  The risk of renal deterioration was similar between ZOMETA 4 mg (15-min infusion) and placebo C

CC39/11-34 Prostate Cancer Overall Summary  ZOMETA ® decreases skeletal complications in men with prostate cancer and bone metastases C

CC39/11-35 ZOMETA ® in Solid Tumors Other Than Prostate Cancer and Breast Cancer (–PC/BC): Placebo-Controlled Trial (011) Prof. Robert Coleman, MD, FRCP Cancer Research Centre Weston Park Hospital Sheffield, England C

CC39/11-36 Solid Tumors –PC/BC Trial Design (1)  Solid tumors other than prostate and breast cancer (–PC/BC) –  1 bone metastasis  Appropriate antineoplastic therapy at study entry  Serum creatinine  3.0 mg/dL (265 µmol/L)  ECOG performance status 0, 1, 2 C

CC39/11-37 Solid Tumors –PC/BC Trial Design (2)  Stratification – Non-small cell lung cancer – Other solid tumors (renal, small cell lung, cancer of unknown primary, bladder, colorectal, head and neck, etc.)  Patients received oral vitamin D 400 IU and calcium 500 mg  Dose and dosing regimen – ZOMETA ® 4 mg, 8/4 mg, and placebo – 5-min amended to 15-min infusion – Every 3 wk  9-mo follow-up C

CC39/11-38 Solid Tumors –PC/BC Demographics and Prognostic Factors ZOMETA ® ZOMETA 4 mg8/4 mg Placebo Demographic factorN = 257N = 266N = 250 Mean age, yr Gender, % male Race Caucasian, % Black, % Performance status ECOG 0 - 1, % Mean FACT-G score NSCLC, n Other solid tumors, n

CC39/11-39 Solid Tumors –PC/BC Patient Disposition 8 ISE T2-3, 4 ZOMETA ® ZOMETA Disposition4 mg8/4 mgPlacebo Intent-to-treat, N Completed study therapy (9 mo) n %

CC39/11-40 Solid Tumors –PC/BC Reasons for Early Discontinuation Patients, % ZOMETA ® ZOMETA 4 mg8/4 mg Placebo Reason for discontinuationN = 257N = 266N = ISE T2-3, 4 Total discontinued prematurely Death Adverse events Withdrew consent Unsatisfactory therapeutic effect Protocol violation Lost to follow-up Other

CC39/11-41 Solid Tumors –PC/BC Proportion (%) of Patients With an SRE Time to First SRE N = 257N = 266N = P =.127 P =.023 Median time, days P-value ZOMETA 4 mg ZOMETA 8/4 mg Placebo163 ZOMETA 4 mg /4 mg Placebo

CC39/11-42 Solid Tumors –PC/BC Components of SRE by Month 9 8 ISE T 2-15; CSR 011 T9-7 N

CC39/11-43 Solid Tumors –PC/BC Mean SMR* ZOMETA 8/4 mgZOMETA® 4 mgPlacebo N = P =.005 P =.069 Mean SMR/yr * + HCM P <.05 for ZOMETA 4 mg and 8/4 mg versus placebo. C

CC39/11-44 Solid Tumors –PC/BC Andersen-Gill Multiple Event Analysis Time to SRE up to Month 9 ZOMETA ® 4 mg ZOMETA 8/4 mg Hazard95% CI forHazard95% CI for Stratumratiohazard ratioratiohazard ratio NSCLC Placebo0.729(0.524, 1.015)0.530(0.377, 0.745) Other solid tumors Placebo0.737(0.493, 1.101)0.886(0.605, 1.298) Total Placebo0.732(0.567, 0.946)0.687(0.531, 0.890) C

CC39/11-45 Other Solid Tumors (011) Proportion of Patients With an SRE in Patients With Different Types of Bone Lesions 57 N =

CC39/11-46 Solid Tumors –PC/BC Disease-Related Endpoints Median time, days ZOMETA ® ZOMETA P-value, 4 mg 8/4 mg Placebo ZOMETA 4 mg EndpointN = 257N = 266N = 250 vs placebo Time to progression of bone lesion, days Time to progression of disease, days C

CC39/11-47 Solid Tumors –PC/BC Quality-of-Life Endpoints Change from baseline, mean  SD ZOMETA ® ZOMETA 4 mg 8/4 mg Placebo Endpoint (9 mo) N = 257N = 266N = 250 Brief pain inventory score § 0.1    2.34 Analgesic score § 0.3    1.08 Performance status (ECOG) § 0.9    1.18 FACT-G total score || –4.7  15.7–2.8  16.7–4.9  16.8 §Increased score = decline. ||Increased score = improvement. C

CC39/11-48 Solid Tumors –PC/BC Efficacy Summary  ZOMETA is the first bisphosphonate to demonstrate efficacy in decreasing skeletal complications in a broad range of solid tumors C Time to Multiple Proportionfirst SREMean skeletalevent analysis with SRE. %(hazard ratio) morbidity ratehazard ratio ZOMETA ® 4 mg N = 257 P-value ZOMETA 8/4 mg N = 266 P-value Placebo — N = 250

CC39/11-49 ZOMETA ® in Solid Tumors Other Than Prostate Cancer and Breast Cancer (–PC/BC): Placebo-Controlled Trial (011) Safety C

CC39/11-50 Primary Cause of Death During the Trial or Within 28 Days After Study Drug Termination § Patients, n (%) ZOMETA ® ZOMETA 4 mg8/4 mgPlacebo Cause of deathN = 254N = 265N = Neoplasms benign/ malignant 33(13.0)43(16.2)52(21.1) Respiratory/thoracic/ mediastinal15(5.9)10(3.8)8(3.2) Cardiac8(3.1)9(3.4)3(1.2) General disorders/ administration site 3(1.2)5(1.9)4(1.6) Infections/infestations6(2.4)6(2.3)4(1.6) Renal/urinary1(0.4)2(0.8)0(0.0) Hepato-biliary disorders0(0.0)1(0.4)0(0.0) ISS T5-12 §6 mo additional data.

CC39/11-51 Solid Tumors –PC/BC Survival – All Patients § ZOMETA 4 mg ZOMETA 8/4 mg Placebo Median time, days ZOMETA ® 4 mg203P =.947 ZOMETA 8/4 mg189P =.471 Placebo E1 PTF p3 35 §6 mo additional data.

CC39/11-52 Safety-evaluable patients, n (%) ZOMETA ® 4 mg ZOMETA 8/4 mgPlacebo Preferred termN = 254N = 265N = 247 Bone pain129 (50.8)130 (49.1)145 (58.7) Nausea116 (45.7)106 (40.0) 83 (33.6) Anemia NOS 94 (37.0) 82 (30.9) 82 (33.2) Vomiting NOS 91 (35.8) 83 (31.3) 71 (28.7) Constipation 85 (33.5) 76 (28.7) 89 (36.0) Dyspnea NOS 83 (32.7) 90 (34.0) 65 (26.3) Fatigue 79 (31.1) 78 (29.4) 72 (29.1) Pyrexia 67 (26.4) 70 (26.4) 56 (22.7) Weakness 66 (26.0) 67 (25.3) 65 (26.3) Anorexia 58 (22.8) 60 (22.6) 62 (25.1) Edema lower limb 56 (22.0) 53 (20.0) 49 (19.8) Malignant neoplasm aggravated 54 (21.3) 67 (25.3) 56 (22.7) Cough 47 (18.5) 44 (16.6) 38 (15.4) Diarrhea NOS 43 (16.9) 48 (18.1) 44 (17.8) Headache NOS 42 (16.5) 36 (13.6) 26 (10.5) Insomnia NEC 42 (16.5) 38 (14.3) 30 (12.1) Dehydration 40 (15.7) 48 (18.1) 41 (16.6) Solid Tumors –PC/BC Incidence of Adverse Events (  15%) Regardless of Study Drug Relationship NOS = Not otherwise specified. NEC = Not elsewhere classified. C

CC39/11-53 Solid Tumors –PC/BC NCI Grade 3/4 Hematology Electrolyte and Mineral Changes  Anemia – Incidence < 5% for all treatment groups, with a slightly higher incidence in the ZOMETA ® treatment groups – Use of red blood cells and erythropoietin was similar for all treatment groups  Electrolyte and mineral adverse events – Incidence of hypocalcemia < 2% for all treatment groups – Higher incidence of hypophosphatemia in the ZOMETA treatment groups 8 Vol 166 ISS PTT 5.1-5

CC39/11-54 Patients Enrolling After the 15-min Amendment NCI Grade 3/4 Serum Creatinine Changes § Patients, n (%) N = 509 ZOMETA ® ZOMETA 4 mg 8/4 mg Placebo N = 165 N = 181 N = 163 Grade 3 1 (0.6)2 (1.1)3 (1.8) Grade 4 2 (1.2)0 (0.0)0 (0.0) C §6 mo additional data.

CC39/11-55 Solid Tumors –PC/BC Kaplan-Meier Estimates of First Serum Creatinine Increase § 011E1 PTF p1 35 §6 mo additional data. ||24% of patients received only 8-mg. ¶51% of patients received only 8 mg. nHazard ratioP-value ZOMETA® 4 mg ZOMETA 8/4 mg || Placebo54 nHazard ratioP-value ZOMETA 4 mg ZOMETA 8/4 mg ¶ Placebo163 Percent of patients (randomized prior to 15-min infusion amendment) Percent of patients (randomized after 15-min infusion amendment)

CC39/11-56 Solid Tumors –PC/BC Safety Summary  Adverse events commonly associated with bisphosphonates (hypophosphatemia, anemias) were reported more frequently in the ZOMETA ® treatment groups  Risk of renal deterioration was moderately higher in the ZOMETA 4-mg treatment group (15-min infusion) than in the placebo group C

CC39/11-57 Solid Tumors –PC/BC Overall Summary  ZOMETA ® is the first bisphosphonate to demonstrate efficacy in decreasing skeletal complications in a broad range of solid tumors  ZOMETA (4 mg via 15-min infusion) has a safety profile similar to i.v. pamidronate 90 mg (historical) C