# Presentation: 882863

## REGULATORY HISTORY of ZOMETA and AREDIA JAW OSTEONECROSIS (ONJ)

- Oncologic Drug Advisory Committee
- March 4, 2005
- Nancy S. Scher, M.D.

## Aredia: Approved Indications

- Treatment of patients with osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma in conjunction with standard antineoplastic therapy
- Hypercalcemia of malignancy
- Paget’s Disease of bone

## Aredia: Approval Dates

- 1991 Hypercalcemia of malignancy
- 1995 Osteolytic lesions of multiple myeloma
- 1996 Osteolytic bone metastases of breast cancer

## Skeletal Related Events (SRE): A Composite Endpoint

- Pathologic fractures
- Radiation therapy to bone
- Surgery to bone
- Spinal cord compression

## Aredia: Randomized Trials1 Multiple Myeloma

- Multiple myeloma indication based on single double-blind, randomized, placebo-controlled trial, n=392, Aredia 90 mg monthly IV x 9 months
- Proportion with SRE: A=24%, P=41% (p<0.001)
- Time to first SRE: A>P (p=0.001)

## Aredia: Randomized Trials2 Breast Cancer

- Two double-blind, randomized, placebo-controlled trials in breast cancer
- Aredia 90 mg IV q3-4 weeks x 24 months
- Patients with ≥1 osteolytic lesion and  receiving concomitant hormonal (n=372) or chemotherapy (n=382)
- Aredia superior to placebo for SRE endpoints

## Zometa: Approved Indications

- Treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy.  Prostate cancer should have progressed after treatment with at least one hormonal therapy.
- Hypercalcemia of malignancy

## Zometa: Approval Dates

- August 2001
- Hypercalcemia of malignancy
- February 2002
- Patients with multiple myeloma and bone metastases from solid tumors, in conjunction with standard antineoplastic therapy.

## Expanded Bone Metastasis Indications for Zometa 

- Multiple myeloma and bone metastases of solid tumors, not limited to breast cancer
- Lesion type not limited to osteolytic
- Optimal duration of therapy not defined

## Zometa: Randomized Trials1

- Oncology indication based on 3 randomized studies
- Multiple myeloma or metastatic breast cancer; Zometa 4 mg vs. Aredia 90 mg q3-4 weeks
- Metastatic prostate cancer; placebo control
- Metastatic solid tumors other than breast or prostate cancer; placebo control
- Primary endpoints:	- Time to first SRE	- Proportion of patients with SRE

## Zometa: Randomized Trials2

| Patient Population
 | Number of Patients | Median
Duration 
Therapy | Control |
| --- | --- | --- | --- |
| MM/Breast Cancer  | 1648 | 12 months | Aredia 90 mg 
 |
| Prostate Cancer | 643 | 10.5 months
 | Placebo |
| Other Solid Tumors | 773 | 3.8 months
 | Placebo |

## Zometa: Randomized Trials3 Time to First SRE

| Study | Study Arm(No. Patients) | Median(days) | Hazard Ratio  (95% CI) | P-value |
| --- | --- | --- | --- | --- |
| Prostate Cancer | Zometa 4 mg
(n = 214)
Placebo
(n=208) |  NR321  | 0.67 
(0.49, 0.91) | 
0.011 |
| Solid Tumors | Zometa 4 mg(n = 257)
Placebo
(n=250) | 230163 | 0.73
 (0.55, 0.96) | 
0.023 |
| MM/Breast Cancer | Zometa 4 mg
(n=561)
Aredia 90 mg
(n=565) | 373

363 | 0.92
(0.77, 1.09) | 
0.32 |

## Number of ONJ Spontaneous Reports to FDA by Year

- 2001
- 0 (1 femoral head)
- 2002
- 9 cases
- 2003
- 60 cases
- 2004 (May)
- 69 cases

## Literature Reports of ONJ Associated with Bisphosphonates

- Rosenberg and Ruggiero 8/03 AAOMS: 26 cases
- Marx 8/03 letter: 36 cases
- Wang 9/03: 3 cases
- Migliorati 11/03 letter JCO: 5 cases
- Ruggiero 5/04: 63 cases
- Estilo 6/04 ASCO: 13/124 chart review
- ASH 12/04: Multiple authors

## Profile of Patients with ONJ

- Diagnosis of malignancy
- No head and neck radiotherapy
- Treatment regimen included IV bisphosphonates
- High proportion had recent invasive dental procedure

## ONJ Labeling ChangesZometa and Aredia 

- Zometa Adverse Events section updated to include ONJ in September 2003 (Aredia October 2003)
- Zometa Precautions section updated August 2004 (Aredia August 2004)

## Zometa Label: Adverse Events

- ONJ reported in patients treated with bisphosphonates
- Majority associated with a dental procedure
- Multiple risk factors for ONJ (e.g. cancer, chemotherapy, radiotherapy, corticosteroids)
- Although causality cannot be determined, prudent to avoid dental surgery, as recovery may be prolonged

## Zometa Label: PRECAUTIONS

- ONJ reported in cancer patients receiving treatment regimens including bisphosphonates
- Many patients were also receiving chemotherapy and corticosteroids
- Majority of cases associated with dental procedures
- Many patients had signs of local infection including osteomyelitis
- Baseline dental exam if risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene)
- While on treatment, avoid invasive dental procedures
- No data if discontinuing therapy reduces risk of ONJ

## Summary

- Zometa and Aredia are effective drugs for the bone metastasis indication
- An unusual adverse event has been identified in some patients treated with IV bisphosphonates
- The true incidence of ONJ is unknown