Denosumab Suppresses Bone Resorption in Breast Ca Mets

ATLANTA —The monoclonal antibody denosumab (AMG 162) attenuates bone resorption in patients with breast cancer who have bone metastases as effectively as bisphosphonates, according to interim results of a trial reported at the 2006 ASCO meeting (abstract 512). The study, which determined the dose for phase III trials, also suggested that the agent is as effective as bisphosphonates in preventing skeletal-related events in these patients.

"RANK ligand is a key mediator in the vicious cycle of bone destruction in metastatic cancer," said Allan Lipton, MD, of the Milton S. Hershey Medical Center. "Denosumab is a fully human monoclonal antibody to RANK ligand. It's a high-affinity IgG₂ antibody that does not bind TNF-α, TNF-β, TRAIL, or CD40 ligand, and can be given subcutaneously."

The 255 women enrolled in the phase II trial had metastatic breast cancer with radiographic evidence of at least one bone metastasis, and had not received any intravenous bisphosphonates. They were randomly assigned to six groups, one receiving intravenous bisphosphonates on an open-label basis, and the others received denosumab subcutaneously on a double-blind basis at five differing doses.

The preplanned interim analysis took place at week 13 of the 25-week trial. Analyses of baseline characteristics showed that about half of the patients enrolled were also receiving chemotherapy and hormonal therapy.

The primary endpoint of the trial was the percentage change in urinary Ntelopeptide (uNTX) level from baseline. The percentage of patients achieving at least a 65% reduction—an endpoint chosen because the literature suggests it is roughly the average reduction achieved with bisphosphonates—was 63% in the bisphosphonate group and 74% in the denosumab groups overall (range across groups, 70% to 76%). The median time to achieving this reduction was 29 days with bisphosphonates vs 13 days with denosumab (range across groups, 10 to 33 days).

The 13-week incidence of skeletal- related events was 16% with bisphosphonates vs 9% with denosumab (range across groups, 7% to 12%), although Dr. Lipton cautioned that the study was not designed to be a comparator study.

Patients in the bisphosphonate group and in the denosumab groups overall had similar rates of grade 3-4 adverse events (33% vs 28%) and similar rates of infection (26% vs 22%). Dr. Lipton reminded the audience that the patients were also receiving chemotherapy and hormonal therapy during the trial. No serious or fatal events have been attributable to either study treatment. Of 13 types of adverse events documented in more than 10% of the study population, 11 occurred with a higher incidence in bisphosphonatetreated patients; only nausea (18% vs 14%) and fatigue (11% vs 9%) were more common with denosumab. Dr. Lipton noted that experience with the antibody is too limited to discern if osteonecrosis of the jaw is a possible adverse effect. "There have been no dose-dependent increases in the incidence of adverse events in denosumab-treated patients," he continued. In addition, none of the patients in the denosumab groups have experienced acute phase or injection site reactions, and none have developed binding or neutralizing antibodies.

"The stated purpose of this trial was to choose a dose for phase III," Dr. Lipton noted. Key factors in this choice were achieving maximal suppression of bone resorption, minimizing escape from this suppression, and selecting a safe and convenient dose. "Taking all these factors into account, the 120 mg every 4 week dosage has been selected," he said.