ODAC Recommends That FDA Approve Zometa for Bone Metastases

ROCKVILLE, Maryland—Members of the Oncologic Drugs Advisory Committee (ODAC) have unanimously recommended that the Food and Drug Administration approve Zometa (zoledronic acid for injection, Novartis) for the treatment of bone metastases in patients with multiple myeloma and breast cancer, prostate cancer, lung cancer, and other solid tumors.

The FDA brought Zometa before ODAC in part because its own oncology division was uncertain about granting such broad approval to the drug.

The 11-to-0 vote came after lengthy presentations by Novartis and FDA medical reviewers and discussions about the merits and meaning of three studies that involved more than 3,000 patients, which the drug company presented to support its application.

"Zometa, given at a dose of 4 mg every 3 to 4 weeks, is bone specific, not tumor specific," said Burkhard Daldrup, PhD, global head of drug regulatory affairs for Novartis’ oncology business unit. "Evidence shows its effectiveness in a broad variety of different tumor types."

Zometa is a new generation of intravenous bisphosphonates, a family of drugs that can inhibit bone resorption. Animal and human studies show Zometa can delay or reduce the occurrence of skeletal-related events (SREs)—which include pathologic fractures, radiation therapy to bone, bone surgery, and spinal cord compression—in patients with bone metastases.

Most patients living with such metastases have either breast or prostate cancer, but lung cancer as well as myeloma, renal cancer, and thyroid cancer frequently result in metastases in the bone.

Aredia (pamidronate disodium for injection, Novartis), used as an adjunct to standard anticancer therapy, is the only bisphosphonate now approved by the FDA for treating multiple myeloma or bone metastases from breast cancer. Zometa is used worldwide to treat hypercalcemia of malignancy, and the FDA approved the drug for that use in the United States on August 20, 2001.

Three Randomized Trials

Novartis presented three randomized phase III trials to support Zometa’s use in reducing SREs in patients with bone metastases from solid tumors and myeloma. Each trial’s protocol called for the use of two different dosages of Zometa, and the primary endpoint for each study was the percentage of patients experiencing any SRE, excluding instances of hypercalcemia of malignancy.

Study 010 was a 13-month, international multicenter, active-control trial that compared Zometa 4 mg, Zometa 8 mg, and Aredia 90 mg in 1,648 breast cancer and multiple myeloma patients. They were randomized and stratified by center and three disease categories: myeloma, breast cancer treated with hormones, and breast cancer treated with chemotherapy. Participants were treated for 1 year, with a 1-month follow-up.

Study 011 enrolled 773 patients with non-small-cell lung cancer (NSCLC) and a wide variety of other solid tumors metastatic to bone—other than breast and prostate cancers—in a 9-month placebo-controlled trial. The protocol called for randomization to Zometa 4 mg, Zometa 8 mg, or placebo. Randomization was stratified as either NSCLC or other tumors.

Study 039, a 15-month, placebo-controlled trial, involved 643 patients who had prostate cancer with rising PSA while on first-line hormonal therapy for metastatic disease. They were randomized to Zometa 4 mg, Zometa 8 mg, or placebo.

After researchers completed accrual for all three trials but while many patients still remained on study, clinical investigators discontinued the Zometa 8 mg dose because of continued renal toxicity. Patients in the 8-mg arms of the studies were switched to 4 mg, and those participants were designated as the Zometa 8/4 mg group in the studies’ efficacy and safety results.

Study Findings

In study 010, patient completion rates were similar among the Zometa 4 mg, Zometa 8/4 mg, and Aredia arms: 62.9%, 59.7%, and 60.7%, respectively. The percentage of patients with SREs was also similar: 44% for Zometa 4 mg and 46% for patients in the other two arms.

Two secondary endpoints of Study 010 also demonstrated the effectiveness of Zometa in breast cancer and myeloma bone metastases, the company said. The time to first SRE was longer in both Zometa groups, compared with the Aredia arm, and the mean skeletal morbidity rate was 1.13 for Zometa 4 mg, 1.08 for Zometa 8/4 mg, and 1.40 for Aredia.

Among patients with NSCLC and other metastatic solid tumors, study 011 found SREs were 38% in the Zometa 4 mg arm, 35% for Zometa 8/4 mg, and 44% for placebo. Only the difference between the Zometa 8/4 mg and placebo groups were statistically significant. The time to first SRE was significantly shorter with Zometa 4 mg (67 days, P = .023). There was no significant difference among the three arms in time to progression of bone lesions or time to progression of disease. There was, however, a delay in the time to progression of bone lesions in the Zometa 4 mg arm of 36 days.

Results from the prostate cancer trial, Study 039, showed that 33% of the Zometa 4 mg, 38% of the Zometa 8/4 mg, and 44% of the placebo patients developed SREs. The difference was not significant between the Zometa 8/4 mg and placebo groups, but it was between the Zometa 4 mg and placebo arms, except for fractures. When results from the two Zometa arms were combined, the SRE rate, compared with placebo, was significantly different. There were no significant differences among the groups in time to progression of bone lesions or time to progression of disease.

All three studies indicated that Zometa was more effective in reducing SREs in patients with osteolytic bone lesions than in those with osteoblastic lesions. They also found no statistically significant differences among patients in the studies in terms of quality of life.

The FDA’s analysis of study 039 suggested that about 1 in 12 prostate cancer patients with bone metastases would benefit from treatment with Zometa. This engendered a discussion about just how significant a benefit the drug might provide in the real world of clinical practice.

"From a clinical perspective, if you prevent 1 patient out of 12 from having severe pain or having pathologic fracture, that’s very clinically relevant," said Philip Bonomi, MD, director of medical oncology, Rush Medical College, Chicago, a nonvoting ODAC advisor.

Dr. Bonomi’s view was echoed by patient representative Eugene J. Kazmierczak, who told the panel, "One in 12 is certainly better than none in 12."

Nonetheless, Derek Raghavan, MD, PhD, associate director, Norris Comprehensive Cancer Center, University of Southern California, and a voting consultant to ODAC, raised a caution. "As a clinician, I’m not sure I know where this drug should find its place," he said. "Everything that has been said about reducing pain is true, but I am not sure that what I’ve heard today will tell me how to apply it in clinical practice. If this drug does get approval, I would ask the FDA to spend some time with the company looking at the development of the package insert and getting the wording right."

Safety Profile

Patients in the three studies generally tolerated Zometa well, and its safety profile proved similar to that of other bisphosphonates. The most common side effect associated with Zometa was a transient set of influenza-like symptoms—fever, arthralgias, myalgias, and chills. Between about 50% and 60% of patients in all arms of all three trials reported bone pain, which in all likelihood was related to their disease and not Zometa.

The renal insufficiency that occurred with Zometa was associated with rapid drug infusion and higher drug dose. Patients who receive Zometa should have periodic evaluations of standard laboratory and clinical parameters of renal function, the company said.