Table 11 describes an overview of the efficacy population in three randomized Zometa trials in patients with multiple myeloma and bone metastases of solid tumors.

These trials included a pamidronate-controlled study in breast cancer and multiple myeloma, a placebo-controlled study in prostate cancer, and a placebo-controlled study in other solid tumors.

The prostate cancer study required documentation of previous bone metastases and 3 consecutive rising PSAs while on hormonal therapy.

The other placebo-controlled solid tumor study included patients with bone metastases from malignancies other than breast cancer and prostate cancer, including NSCLC, renal cell cancer, small cell lung cancer, colorectal cancer, bladder cancer, GI/genitourinary cancer, head and neck cancer, and others.

These trials were comprised of a core phase and an extension phase.

In the solid tumor, breast cancer and multiple myeloma trials, only the core phase was evaluated for efficacy as a high percentage of patients did not choose to participate in the extension phase.

In the prostate cancer trials, both the core and extension phases were evaluated for efficacy showing the Zometa effect during the first 15 months was maintained without decrement or improvement for another 9 months.

The design of these clinical trials does not permit assessment of whether more than one-year administration of Zometa is beneficial.

The optimal duration of Zometa administration is not known.      The studies were amended twice because of renal toxicity.

The Zometa infusion duration was increased from 5 minutes to 15 minutes.

After all patients had been accrued, but while dosing and follow-up continued, patients in the 8 mg Zometa treatment arm were switched to 4 mg due to toxicity.

Patients who were randomized to the Zometa 8 mg group are not included in these analyses.Table 11: Overview of Efficacy Population for Phase III Studies Patient PopulationNo.

of PatientsZometa DoseControlMedian Duration (Planned Duration) Zometa 4 mg Multiple myeloma or metastatic breast cancer1,6484 and 8* mg Q3-4 weeksPamidronate 90 mg Q3-4 weeks12.0 months (13 months) Metastatic prostate cancer6434 and 8* mg Q3 weeksPlacebo10.5 months (15 months) Metastatic solid tumor other than breast or prostate cancer7734 and 8* mg Q3 weeksPlacebo3.8 months (9 months) * Patients who were randomized to the 8 mg Zometa group are not included in any of the analyses in this package insert.       Each study evaluated skeletal-related events (SREs), defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression.

Change in antineoplastic therapy due to increased pain was a SRE in the prostate cancer study only.

Planned analyses included the proportion of patients with a SRE during the study and time to the first SRE.

Results for the two Zometa placebo-controlled studies are given in Table 12.Table 12: Zometa Compared to Placebo in Patients with Bone Metastases from Prostate Cancer or Other Solid Tumors I.

Analysis of Proportion of Patients with a SRE1II.

Analysis of Time to the First SRE StudyStudy Arm & Patient NumberProportionDifference2 & 95% CIP-valueMedian (Days)Hazard Ratio3 & 95% CIP-value Prostate CancerZometa 4 mg (n=214)33%-11% (-20%, -1%)0.02Not Reached0.67 (0.49, 0.91)0.011 Placebo (n=208)44%321 Solid TumorsZometa 4 mg (n=257)38%-7% (-15%, 2%)0.132300.73 (0.55, 0.96)0.023 Placebo (n=250)44%163 1SRE=Skeletal-Related Event2Difference for the proportion of patients with a SRE of Zometa 4 mg versus placebo.3Hazard ratio for the first occurrence of a SRE of Zometa 4 mg versus placebo.       In the breast cancer and myeloma trial, efficacy was determined by a noninferiority analysis comparing Zometa to pamidronate 90 mg for the proportion of patients with a SRE.

This analysis required an estimation of pamidronate efficacy.

Historical data from 1,128 patients in three pamidronate placebo-controlled trials demonstrated that pamidronate decreased the proportion of patients with a SRE by 13.1% (95% CI = 7.3%, 18.9%).

Results of the comparison of treatment with Zometa compared to pamidronate are given in Table 13.Table 13: Zometa Compared to Pamidronate in Patients with Multiple Myeloma or Bone Metastases from Breast Cancer I.

Analysis of Proportion of Patients with a SRE1II.