# Presentation: 737372

## ZOMETA® in Breast Cancer and Multiple Myeloma: Pamidronate-Controlled Trial (010)

**James Berenson, MD****Cedars-Sinai Medical Center****Los Angeles, California**** **

**C**

## Breast Cancer and Multiple MyelomaTrial Design (1)

**Double-blind, double-dummy **
**Stratification**
**Durie-Salmon Stage III multiple myeloma with******** 1 osteolytic lesion**
**Chemotherapy**
**Hormonal therapy**
**Appropriate antineoplastic therapy at baseline and during the course of the trial **
**ECOG performance status 0, 1, 2**
**Serum creatinine ******** 3.0 mg/dL (265 μmol/L)**

**C**

**Stage IV breast cancer with ******** 1****osteolytic, osteoblastic, or mixed lesion**

## Breast Cancer and Multiple MyelomaTrial Design (2)

**12-mo dosing regimen**
**Pamidronate 90 mg every 3 to 4 wk/****120-min infusion**
**ZOMETA****®**** 4 mg and 8/4 mg every 3 to 4 wk/****5-min amended to 15-min infusion**
**Study duration of 13 mo **
**Patients received oral vitamin D 400 IU and calcium 500 mg**

**C**

## Breast Cancer and Multiple MyelomaStudy Objectives

**Primary objective**
**Demonstrate the effectiveness of ZOMETA****®**** through the noninferiority****§**** comparison to pamidronate for the treatment of bone metastases**
**Demonstrate safety profile of ZOMETA comparable to pamidronate**

**3**

**§Margin of 8% with 2-sided 95% confidence intervals based on**
**the results of pamidronate bone metastases registration trials.**

## Breast Cancer and Multiple MyelomaStudy Endpoints (1)

**Primary endpoint**
**Proportion (%) of patients experiencing any skeletal-related event (SRE) not including hypercalcemia of malignancy (HCM)**

**C**

## Breast Cancer and Multiple Myeloma Study Endpoints (2)

**Breast Cancer and Multiple Myeloma ****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**

## Breast Cancer and Multiple Myeloma 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**
***Hypercalcemia of malignancy (HCM)***

**C**

## Breast Cancer and Multiple Myeloma 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**

**§Skeletal events occurring within 21 days counted as a single occurrence.**

**C**

## Clinical Trial History

**Original study design**
**ZOMETA****®**** (4 mg or 8 mg) via 5-min infusion versus pamidronate 90 mg infused over 120 min every 3 to 4 wk for 12 mo**
**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 pamidronate 90 mg**

**C**

## Clinical Trial History Breast Cancer and Multiple Myeloma (010)

**Clinical Trial History ****Breast Cancer and Multiple Myeloma (010)**

**29**

**6/98**

**12/98**

**6/99**

**6/00**

**12/00**

**12/99**

**Accrual**

**1/01**

**Treatment and follow-up**

## Breast Cancer and Multiple Myeloma Demographics and Prognostic Factors

**	****	**** ****ZOMETA****®****  ****	****ZOMETA****	****Pam****	****	****	****4 mg****	****8/4 mg****	****90 mg**
**Demographic factor****	****N = 561****	****N = 524****	****N = 555****  **
**Mean age, yr****	****59.7****	****58.9****	****58.8**
**Gender, % female****	****81.5****	****81.7****	****83.5**
**Race, % Caucasian****	****87.9****	****84.4****	****87.1**
**Performance status**
**	****ECOG 0 - 1, %****	****84.5****	****81.9****	****78.6**
**Breast cancer**
**	****Chemotherapy, n ****	****178****	****172****	****181****	**
**	****Hormonal therapy, n ****	****200****	****192****	****207****	**
**Multiple myeloma, n  ****	****183****	****160****	****167**

**31**

**Treatment groups were generally well balanced for prior skeletal complications, prognostic factors, and prior therapy**

## Breast Cancer and Multiple Myeloma Patient Disposition

**	****	****	**
**	****	****ZOMETA****®****	**** ****ZOMETA****	****Pam**
**Disposition****	****4 mg****	****8/4 mg****	****90 mg**
**Intent-to-treat, N****	****561****	****524****	****555**
**Completed study****therapy (13 mo)**
**	****   ****n****	****353****	****313****	****337**
**	****   ****% ****	****62.9****	****59.7****	****60.7**

**8**

- ISE  T2-27, 28

## Breast Cancer and Multiple Myeloma Reasons for Early Discontinuation

**	****	****Patients, %****	**
**	**** ****ZOMETA****®**** ****	**** ZOMETA ****	**** Pam ****	**** 4 mg ****	**** 8/4 mg ****	**** 90 mg ****Reason for discontinuation****	**** N = 561 ****	**** N = 524 ****	**** N = 555**
**Total discontinued prematurely****	****37.1****	****40.3****	****39.3**
**Death****	****10.7****	****10.7****	****11.5**
**Adverse events****	****10.2****	****13.4****	****  9.2**
**Withdrew consent****	****  8.4****	****  8.6****	****10.1**
**Unsatisfactory therapeutic effect****	****  3.2****	****  3.4****	****  4.0  **
**Condition no longer****	****  ****required study drug****	****  1.1****	****  1.3****	****  1.4 **
**Protocol violation****	****  1.1****	****  0.8****	****  0.7**
**Others****	****  2.5****	****  2.2****	****  2.3**

**8**

- ISE  T2-27, 28

## Breast Cancer and Multiple Myeloma Proportion (%) of Patients With an SRE 

**N =**

**561**

**524**

**555**

**ZOMETA 4 mg versus pamidronate 90 mg: 95% CI (–7.9%,**** 3.7%****). The noninferiority criterion, the upper boundary of the 95% CI, is below 8%**

## Noninferiority Margin for Study 010(Using Pamidronate 12, 18, and 19)

**Noninferiority Margin for Study 010****(Using Pamidronate 12, 18, and 19)**

**	****           ****% with SRE ****	****         Placebo vs Pam 90 mg ****	**
**Patients****	****Placebo****	****Pam****	****Diff****	****95% CI****	****margin**
**All****	****52.0****	****38.9****	****13.1****	****(****7.3****, 18.9)****	****3.65**

**32**

**Pt 91-2AR1**

**Conservative**

**12, 18, 19:   (Placebo – Pam)**

**010:   (ZOMETA – Pam)**

**0**

**(**

**)**

*****

**3.65**

**7.3**

**13.1**

**18.9**

**0**

**(**

**)**

**–****7.9**

**3.7**

**–****2.0**

**PAM**

**PAM**

**Placebo**

**ZOM**

## Breast Cancer and Multiple Myeloma Components of SRE by Month 13 

**8**

- ISE T 2-40; CSR 010 T9-7

** ****N **
**561**
**524**
**555**

## Breast Cancer and Multiple Myeloma Time to First SRE

**ZOMETA 4 mg****	****561****	****	****354****	****	****279****	****	****185****	****11**
**ZOMETA 8/4 mg****	****524****	****	****334****	****	****238****	****	****154****	****12**
**Pam 90 mg****	****555****	****	****361****	****	****239****	****	****153****	****5**

**	**
**ZOMETA****®**** 4 mg****	****373****	****0.915 (0.786, 1.090)**
**ZOMETA 8/4 mg****	****353****	****0.994 (0.834, 1.185)**
**Pam 90 mg****	****363**

- 010 PTF 9.2-1p4; CSR 010 T9-3

- 14

**Median time,****days**

**Hazard ratio****§****(95% CI)**

**§ZOMETA 4 mg, ZOMETA 8/4 mg versus pamidronate 90 mg.**

## Breast Cancer and Multiple Myeloma Mean SMR

**561**

**524**

**555**

**N =**

## Breast Cancer and Multiple MyelomaAndersen-Gill Multiple Event Analysis Time to SRE up to Month 13

**	****                       ****ZOMETA****®**** 4 mg****	****               ZOMETA 8/4 mg**
**	****Hazard****	****95% CI for****	****Hazard****	****95% CI for****	****ratio****	****hazard ratio****	****ratio****	****hazard ratio**
**Pam 90 mg****	****0.885****	****(0.748, 1.047)****	****0.910****	****(0.768, 1.079)**
**ZOMETA 4 mg****	****	****	****1.025****	****(0.863, 1.218)**

**C**

## Breast Cancer (010)Proportion of Patients With an SRE Patients With Different Types of Bone Lesions

**57**

**N = **

**190**

**176**

**117**

**143**

**71**

**64**

**162**

**124**

**83**

## Breast Cancer and Multiple Myeloma Disease- and QOL-Related Endpoints 

**Comparable disease and QOL-related measures were demonstrated for the ZOMETA****®**** and pamidronate arms**
**Time to progression of bone metastases**
**Time to overall progression of disease**
**Pain and analgesic scores**
**ECOG performance status**
**Global quality of life**

**C**

## Breast Cancer and Multiple Myeloma Disease-Related Endpoints 

**	****	****Median time, days **
**	****	****	****	****	**** ****ZOMETA****®**** ****	**** ZOMETA ****	****Pam ****	**** 4 mg ****	**** 8/4 mg ****	**** 90 mg****	**
**Endpoint****	****N = 561****	**** N = 524 ****	****N = 555****	**
**Time to progression****	****	****	****	****of bone lesion, days****	****179.0****	****175.0****	****171.0**
**Time to progression****	****	****	****	****of disease, days****	**** 134.0 ****	**** 125.0 ****	**** 111.0 **

- CSR 010 T9-14

**C**

## Breast Cancer and Multiple Myeloma Quality-of-Life Endpoints

**||Increased score = improvement.**

**Breast Cancer and Multiple Myeloma ****Quality-of-Life Endpoints**

**	****                                             ****Change from baseline, mean ******** SD **
**	****ZOMETA****®**** ****	****ZOMETA ****	****Pam ****	****4 mg****	**** 8/4 mg****	****90 mg****	**** Endpoint (13 mo) ****	****N = 561****	****N = 524****	****N = 555**
**Brief pain inventory score****§****	****–0.5 ******** 2.06****	****–0.6 ******** 2.20****	****–0.4 ******** 2.13**
**Analgesic score****§**** ****	****–0.1 ******** 1.41****	****–0.1 ******** 1.44****	****–0.1 ******** 1.41**
**Performance status (ECOG)****§**** ****	****  0.3 ******** 1.04****	****  0.3 ******** 1.05****	****  0.4 ******** 1.09**
**FACT-G total score****||****	****  0.5 ******** 14.9 ****	****  3.1 ******** 14.9 ****	****  2.1 ******** 15.6**
**      **

- CSR 010 T9-10, 9-11, 9-12, 9-13

**C**

## Breast Cancer and Multiple Myeloma Efficacy Summary 

**ZOMETA demonstrated comparable efficacy to pamidronate (noninferiority) in preventing skeletal-related events**

**C**

**	****	****Time to ****	****	****Multiple****	****	****Proportion****	****first SRE****	****Mean skeletal****	****event analysis ****	****with SRE, %****	****(hazard ratio)****	****morbidity rate****	****hazard ratio**
**ZOMETA****®**** 4 mg****	****44****	****0.915****	****1.13****	****0.885****	**
**ZOMETA 8/4 mg****	****46****	****0.994****	****1.08****	****0.910****	**
**Pam 90 mg****	****46****	****—****	****1.40****	****—****	****	**

## ZOMETA® in Breast Cancer and Multiple Myeloma:Pamidronate-Controlled Trial (010)

**Safety**

## Primary Cause of Death During theTrial or Within 28 Days After Study Drug Termination§

**	****	****Patients, n (%)**
**	****ZOMETA****®****	****ZOMETA****	****Pam**
**	****4 mg****	****8/4 mg****	****90 mg****Cause of death****	****N = 563****	****N = 524****	****N = 556**

**8**

**Neoplasms benign/****	****malignant****	**** 54****	****(9.6)****	****40****	****(7.6)****	****47****	****(8.5)**
**Respiratory/thoracic/****	****mediastinal****	****4****	****(0.7)****	****6****	****(1.1)****	****9****	****(1.6) **
**Cardiac****	****7****	****(1.2)****	****6****	****(1.1)****	****9****	****(1.6)**
**General disorders/****	****administration site ****	****3****	****(0.5)****	****1****	****(0.2)****	****5****	****(0.9)**
**Infections/infestations****	****11****	****(2.0)****	****8****	****(1.5)****	****10****	****(1.8)**
**Renal/urinary****	****0****	****(0.0)****	****4****	****(0.8)****	****0****	****(0.0)**
**Hepato-biliary disorders****	****3****	****(0.5)****	****1****	****(0.2)****	****0****	****(0.0)****	**

- ISS T5-12

**§6 mo additional data.**

## Breast Cancer and Multiple Myeloma Survival – All Patients§

**ZOMETA 4 mg****	****563****	****519****	****479****	****435****	****379****	****308****	****160****	****61**
**ZOMETA 8/4 mg****	****524****	****486****	****438****	****396****	****338****	****270****	****154****	****64**
**Pam 90 mg****	****556****	****526****	****466****	****416****	****363****	****309****	****175****	****58**

**	****Median time, days**
**ZOMETA****®**** 4 mg****	****838****	*****P***** = .843**
**ZOMETA 8/4 mg****	****830****	*****P***** = .516**
**Pam 90 mg****	****811**

- 010E1 PTF 10.5-1p4

**35**

**§6 mo additional data.**

## Breast Cancer and Multiple Myeloma Incidence of Adverse Events ( 15%)Regardless of Study Drug Relationship

**	****	****ZOMETA****®**** 4 mg****	**** ZOMETA 8/4 mg****	****Pam 90 mg**
**Preferred term****	****N = 563****	****N = 524****	****N = 556**
**Bone pain****	****312 (55.4)****	****276 (52.7)****	****302 (54.5)**
**Nausea****	****250 (44.4)****	****240 (45.8)****	****245 (44.1)**
**Fatigue****	****217 (38.5)****	****192 (36.6)****	****212 (38.1)**
**Pyrexia****	****200 (35.5)****	****180 (34.4)****	****160 (28.8)**
**Vomiting NOS****	****166 (29.5)****	****158 (30.2)****	****164 (29.5)**
**Anemia NOS****	****153 (27.2)****	****155 (29.6)****	****155 (27.9)**
**Myalgia****	****144 (25.6)****	****119 (22.7)****	****130 (23.4)**
**Diarrhea NOS****	****141 (25.0)****	****138 (26.3)****	****139 (25.0)**
**Dyspnea NOS****	****138 (24.5)****	****110 (21.0)****	****134 (24.1)**
**Cough****	****135 (24.0)****	****101 (19.3)****	****114 (20.5)**
**Constipation****	****134 (23.8)****	****130 (24.8)****	****132 (23.7)**
**Arthralgia****	****125 (22.2)****	****  98 (18.7)****	****  95 (17.1)**
**Weakness****	****113 (20.1)****	****  93 (17.7)****	****  91 (16.4)**
**Headache NOS****	****106 (18.8)****	****113 (21.6)****	****131 (23.6)**
**Anorexia****	****105 (18.7)****	****  83 (15.8)****	****  70 (12.6)**
**Edema lower limb****	****  92 (16.3)****	****  83 (15.8)****	****108 (19.4)**
**Alopecia****	****  89 (15.8)****	****  73 (13.9)****	****  72 (12.9)**
**Neutropenia****	****  84 (14.9)****	****  80 (15.3)****	****  77 (13.8)**
**Insomnia NEC****	****  80 (14.2)****	****  78 (14.9)****	****  94 (16.9)**
**Back pain****	****  60 (10.7)****	****  82 (15.6)****	****  72 (12.9)**

**Breast Cancer and Multiple Myeloma ****Incidence of Adverse Events (******** 15%)****Regardless of Study Drug Relationship**

**NOS = Not otherwise specified. **
**NEC = Not elsewhere classified.**

**C**

## Breast Cancer and Multiple MyelomaNCI Grade 3/4 HematologyElectrolyte and Mineral Changes

**Anemia **
**Incidence < 6% for all treatment groups**
**No differences between treatment groups**
**Use of red blood cells and erythropoietin was similar for all treatment groups**
**Electrolyte and mineral adverse events**
**Incidence < 10% in all treatment groups**
**Most common events in the ZOMETA****®**** 4 mg treatment group were hypophosphatemia, hypokalemia, and hyperkalemia**

**8**

- Vol 166 ISS PTT 5.1-5

## Breast Cancer and Multiple MyelomaDefinition of Serum Creatinine Increase 

**Breast Cancer and Multiple Myeloma****Definition of Serum Creatinine Increase **

**Serum creatinine normal (< 1.4 mg/dL) and an increase of 0.5 mg/dL**
**Serum creatinine abnormal (******** 1.4 mg/dL) and an increase of 1.0 mg/dL**
**Doubling of serum creatinine baseline value**
**If serum creatinine was increased, dose was held**
**until within 10% of the baseline serum level**

**48**

## Breast Cancer and Multiple Myeloma Kaplan-Meier Estimates of First Serum Creatinine Increase§

**	****n ****	**** ****Hazard ratio****	*****P*****-value**** **
**ZOMETA****®**** 4 mg****	****272****	****2.338****	****  .003**
**ZOMETA 8/4 mg****||**** ****	****240****	****3.580****	****  .001**
**Pam 90 mg****	****270**

- 010E1 PTF 10.6-2p1

**35**

**	****n****	****Hazard ratio****	*****P*****-value**
**ZOMETA 4 mg****	****272****	****1.012****	****  .965**
**ZOMETA 8/4 mg****¶**** ****	****263****	****2.191****	****  .001**
**Pam 90 mg****	****268**

**Percent of****patients without****increase****(randomized****prior to 15-min****infusion****amendment)**

**Percent of****patients without****increase****(randomized****after 15-min****infusion****amendment)**

**§6 mo additional data.****||****46% of patients received only 8-mg. **
**¶21% of patients received only 8 mg.**

## Breast Cancer and Multiple MyelomaPatients Enrolling After the 15-min Amendment NCI Grade 3/4 Serum Creatinine Changes§

**	****	**** ****Patients, n (%)****	****	****	****	****	****	****N = 803**
**	****  ****ZOMETA****®**** ****	**** ZOMETA ****	**** Pam****	****	****	**** 4 mg****	**** 8/4 mg****	****90 mg****	****	****	**** N = 272****	****N = 263****	****N = 268**
**Grade 3****	****  1 (0.4)****	****6 (2.3)****	****4 (1.5)**
**Grade 4****	****  0 (0.0)****	****1 (0.4)****	****1 (0.4)**

**C**

**§6 mo additional data.**

## Breast Cancer and Multiple Myeloma Safety Summary	

**ZOMETA****®**** (4 mg via 15-min infusion) has a safety profile, including renal effects, comparable to i.v. pamidronate (90 mg over 120 min) dosed every 3 to 4 weeks**

**C**

## Breast Cancer and Multiple Myeloma Overall Summary	

**ZOMETA****®**** ****4 mg via 15-min infusion every 3 to 4 weeks ****demonstrated comparable safety and efficacy (noninferiority) to pamidronate 90 mg over 120 min in treating bone metastases in breast cancer and osteolytic lesions in multiple myeloma**

**C**