CR-1

Clinical Benefit of Bisphosphonates for Cancer Patients with Metastatic Bone

Disease

Clinical Benefit of Bisphosphonates for Cancer Patients with Metastatic Bone

Disease

James R. Berenson, MD

Medical & Scientific Director

Institute for Myeloma & Bone Cancer Research

Los Angeles, California

James R. Berenson, MD

Medical & Scientific Director

Institute for Myeloma & Bone Cancer Research

Los Angeles, California

CR-2

Metastatic Bone Disease: Scope of the ProblemMetastatic Bone Disease: Scope of the Problem

Extremely common - > 500,000 patients in USA– Myeloma - > 90%– Breast - two thirds of patients– Prostate - two thirds of patients– Lung - one third of patients

Median survival measured in years, not weeks or months

Major clinical consequences for patients, families, and society

Extremely common - > 500,000 patients in USA– Myeloma - > 90%– Breast - two thirds of patients– Prostate - two thirds of patients– Lung - one third of patients

Median survival measured in years, not weeks or months

Major clinical consequences for patients, families, and society

CR-3

Clinical Consequences of Metastatic Bone Disease† Clinical Consequences of Metastatic Bone Disease†

Pathologic fractures 10 - 25 Spinal cord compression/collapse 3 - 5 Radiation therapy 15 - 20 Surgery to bone 5 - 10 Hypercalcemia 2 - 10 Bone pain 50 Use of analgesics 40 Quality-of-life effects Survival

Pathologic fractures 10 - 25 Spinal cord compression/collapse 3 - 5 Radiation therapy 15 - 20 Surgery to bone 5 - 10 Hypercalcemia 2 - 10 Bone pain 50 Use of analgesics 40 Quality-of-life effects Survival

% of patients/yr

SREs

SREs = Skeletal-related events.

† From PLAC arms of randomized clinical trials with Aredia® or Zometa®.

CR-4IV Bisphosphonates—Major Impact in Reducing Skeletal Complications for Cancer Patients With Metastatic Bone Disease

IV Bisphosphonates—Major Impact in Reducing Skeletal Complications for Cancer Patients With Metastatic Bone Disease

% with SRE # SREs per yr

Placebo BP %† Placebo BP %

Prostate(Saad et al.)

49 Z-38 22* 1.5 0.7 47*

Breast (Hortobagyi et al.)

(Kohno et al.)

64

50

A-51

Z-30

20*

40*

3.7

1.42

2.4

0.7

35*

50*

Myeloma (Berenson et al.)

51 A-38 26* 2.0 1.0 50*

Others(Rosen et al.)

46 Z-39 15 2.7 1.7 37*

SRE = Skeletal-related event; Pbo = Placebo; BP = Bisphosphonate; Z = Zometa®; A = Aredia®; * P < 0.05; † Relative decrease

CR-5

Breast Cancer and Multiple Myeloma Efficacy Summary† Breast Cancer and Multiple Myeloma Efficacy Summary†

Proportionwith SRE, %

Time to first SRE (median)‡

Mean skeletal morbidity rate‡

Multiple event analysis

Hazard ratio‡

Zometa® 4 mg 47 376 1.04 0.841

Aredia® 90 mg 51 356 1.39 —

P value .243 .151 .084 .030

† Rosen LS, et al. Cancer. 2003;98:1735–1744.‡ Hypercalcemia of malignancy (included as a skeletal-related event).

CR-6

Benefits of IV Bisphosphonates in Metastatic Bone DiseaseBenefits of IV Bisphosphonates in Metastatic Bone Disease

Reduce skeletal complications

– Aredia®

• Breast cancer and myeloma with lytic lesions

• Ineffective in prostate cancer

• Not tested in other tumor types

– Zometa®

• Breast cancer, myeloma, and prostate cancer

• Tested and effective in other tumor types

Decrease pain and analgesic use

Prevent deterioration of quality of life

Reduce skeletal complications

– Aredia®

• Breast cancer and myeloma with lytic lesions

• Ineffective in prostate cancer

• Not tested in other tumor types

– Zometa®

• Breast cancer, myeloma, and prostate cancer

• Tested and effective in other tumor types

Decrease pain and analgesic use

Prevent deterioration of quality of life

CR-7

ONJ in Myeloma Patients—The IMBCR Experience ONJ in Myeloma Patients—The IMBCR Experience

6 cases of ONJ Range of severity

– 3 patients required intermittent antibiotics (Aredia + Zometa, Zometa only in 2) - remain on bisphosphonate treatment

– 1 patient recently diagnosed with minor temporary discomfort (Aredia only) - remains on treatment

• Largely resolved with clarithromycin PO

– 2 patients (Aredia + Zometa, Zometa only) discontinued bisphosphonate secondary to significant effect on mastication

Status of myeloma

– 3 in long-term complete remission (auto-PSCT, VAD, thalidomide)

– 1 in near complete remission (on steroids)

– 2 with long-term indolent myeloma requiring no other therapy

• 1 patient with 40% reduction in M-protein for > 4 yr

6 cases of ONJ Range of severity

– 3 patients required intermittent antibiotics (Aredia + Zometa, Zometa only in 2) - remain on bisphosphonate treatment

– 1 patient recently diagnosed with minor temporary discomfort (Aredia only) - remains on treatment

• Largely resolved with clarithromycin PO

– 2 patients (Aredia + Zometa, Zometa only) discontinued bisphosphonate secondary to significant effect on mastication

Status of myeloma

– 3 in long-term complete remission (auto-PSCT, VAD, thalidomide)

– 1 in near complete remission (on steroids)

– 2 with long-term indolent myeloma requiring no other therapy

• 1 patient with 40% reduction in M-protein for > 4 yr

CR-8

Perspective—IV Bisphosphonates in Cancer Patients with Bone InvolvementPerspective—IV Bisphosphonates in Cancer Patients with Bone Involvement

Skeletal complications have profound effects on the lives of patients with metastatic bone disease

IV bisphosphonate (Zometa® and Aredia®)

– Reduce bony complications

• Number of events/yr one third to one half

• Percent of patients with events by 15% to 40%

– Decrease bone pain, reduce pain meds, and prevent deterioration in QOL

Skeletal complications have profound effects on the lives of patients with metastatic bone disease

IV bisphosphonate (Zometa® and Aredia®)

– Reduce bony complications

• Number of events/yr one third to one half

• Percent of patients with events by 15% to 40%

– Decrease bone pain, reduce pain meds, and prevent deterioration in QOL

CR-9

Perspective—IV Bisphosphonates in Cancer Patients with Bone InvolvementPerspective—IV Bisphosphonates in Cancer Patients with Bone Involvement

Patients receiving IV bisphosphonates (Zometa and Aredia)

– Infrequently develop any form of ONJ (0.1% to 2%/yr)

– Severity varies; most patients improve while continuing bisphosphonate therapy

ONJ risk minor - rarely clinically significant compared with major problems that frequently occur without Aredia or Zometa treatment (eg, fractures, spinal cord compression, radiation therapy, or surgery)

Patients receiving IV bisphosphonates (Zometa and Aredia)

– Infrequently develop any form of ONJ (0.1% to 2%/yr)

– Severity varies; most patients improve while continuing bisphosphonate therapy

ONJ risk minor - rarely clinically significant compared with major problems that frequently occur without Aredia or Zometa treatment (eg, fractures, spinal cord compression, radiation therapy, or surgery)

CR-10

IV Bisphosphonates for Patients With Metastatic Bone Disease—Benefits vs RisksIV Bisphosphonates for Patients With Metastatic Bone Disease—Benefits vs Risks

Benefits Risks

Fractures

Radiotherapy

Bone pain

ONJ ?

Renal (infrequent)

Humeral fracture in a myeloma patient