Denosumab: Nonsurgery Option for Giant Cell Tumor of Bone

Fran Lowry

July 25, 2013

In June 2013, the US Food and Drug Administration (FDA) announced that it was expanding the approved use of denosumab (Xgeva, Amgen) to include the treatment of adults and adolescents with giant cell tumor of bone (GCTB).

"Denosumab provides a needed treatment option for patients with GCTB who are not surgical candidates or who would otherwise have to undergo extensive, life-altering surgery," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products at the FDA Center for Drug Evaluation and Research.

The FDA reviewed denosumab as an orphan product under its priority review program, as reported by Medscape Medical News. The safety and efficacy data from the phase 2 study of denosumab that helped inform the FDA's decision were published online July 16 in the Lancet Oncology.

Principal investigator of that phase 2 trial, Sant Chawla, MD, from the Sarcoma Oncology Center in Santa Monica, California, explained the 3 reasons for the speedy approval of denosumab.

"Number 1, there is no other effective treatment. Number 2, it is a very rational and targeted drug. Number 3, giant cell tumor of bone is a disease of young people, between 15 and 40 to 50 years, two thirds of whom are females; it doesn't happen in older people. Plus, overall toxicity is minimum," Dr. Chawla said.

Now that the drug has been approved for this indication, there is no need for a phase 3 randomized trial. He noted that "it would be unethical not to give this drug to patients who have recurrence or where the tumor is in the spine or another area where it cannot easily be resected or it has metastasized."

Clinical Trial Results

The initial investigation of denosumab in GCTB was a phase 1 study conducted in Australia and funded by Amgen (Lancet Oncol. 2010;11:275-280).

In the phase 1 study, 30 of 35 evaluable patients (86%) with recurrent or unresectable GCTB showed a tumor response, defined as the elimination of at least 90% of giant cells or no radiologic progression of the target lesions up to week 25. Histology results, which were available for 20 patients, showed complete or near complete elimination of giant cells, and radiologic results showed a lack of progression or stable disease in 10 of 15 patients in whom radiologic results were available.

In the phase 2 study, also funded by Amgen, 3 groups of patients were evaluated: 170 patients had disease that was surgically unsalvageable; 101 patients had salvageable GCTB but the surgery was associated with severe morbidity; and 11 patients were transferred from the phase 1 study of denosumab.

Patients in the unsalvageable and salvageable groups received subcutaneous denosumab 120 mg every 4 weeks with loading doses on days 8 and 15 of the first cycle. Those in the phase 1 extension group continued their regimen from the previous study.

The primary end point was the safety profile of denosumab in terms of adverse events and laboratory abnormalities. The secondary end points included time to disease progression in the unsalvageable group, and the proportion of patients who were able to avoid surgery at 6 months in the salvageable group.

Osteonecrosis of the jaw occurred in 3 of the 281 patients (1%) who were analyzable for safety, and 15 (5%) patients developed hypocalcemia.

The most common grade 3/4 adverse events were hypophosphatemia (in 9 patients), anemia (3 patients), back pain (3 patients), and pain in extremities (3 patients).

Serious adverse events occurred in 25 patients. There were no treatment-related deaths.

There was no disease progression in 163 of 169 patients (96%) in the unsalvageable group after a median follow-up of 13 months (interquartile range [IQR], 5.8 - 21.0).

In the salvageable group, 74 of 100 (74%) analyzable patients had been able to forego surgery at a median follow-up of 9.2 months (IQR, 4.2 - 12.9), and 16 of 26 patients (62%) had less extensive surgery than had been planned.

All Patients With GCTB Will Benefit

Dr. Chawla said he is very satisfied with these results. "Pretty much everybody with giant cell tumor of bone will benefit from denosumab. Most orthopedic oncologists, who generally see this disease, should know that they do not have to be that aggressive with this tumor now. They can resect what can be easily resected without morbidity and then use a drug that is pretty effective to eliminate the residual giant cells," he said.

Study Has Limitations

In an accompanying comment, Maurice Balke, MD, from the University of Witten-Herdecke, Cologne-Merheim Medical Centre, in Germany, writes that although he agrees with Dr. Chawla and colleagues on most points, the study does have several limitations.

Dr. Balke claims that the follow-up of "roughly 1 year is too short to reliably prove efficacy in complicated cases of GCTB."

He agrees that it would be unethical to compare denosumab with placebo in patients with such severe illness, "but comparison with bisphosphonates, which are generally a lot less expensive than denosumab, would be reasonable."

Finally, Dr. Balke cautions that the results of this study should be "assessed with care because Amgen, which funded the study, was strongly involved in study design and assessment and interpretation of data."

He calls for more independent studies with longer follow-ups to confirm "these encouraging results."

The study was funded by Amgen. Dr. Chawla reports financial relationships with Amgen. Dr. Balke has disclosed no relevant financial relationships.

Lancet Oncol. Published online July 16, 2013. Abstract, Comment

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