DENOSUMAB FOR GIANT CELL TUMORS

February 11, 2010 — The novel biologic agent denosumab (Amgen) could offer a breakthrough in the treatment of the rare giant cell tumor of bone, suggests an editorial published online February 10 in The Lancet Oncology. It accompanies the publication of a small open study, which reports that the drug produced a tumor response in 30 of 35 patients (86%).

"To our knowledge, this is the first report that clearly shows a promising systemic treatment option for this rare type of tumor," write the editorialists, Maurice Balke, MD, and Jendrik Hardes, MD, from the Department of Trauma and Orthopedic Surgery at the University of Witten-Herdecke in Cologne, Germany. There have been reports of beneficial effects with bisphosphonates, but no successive prospective trials, they add.

The current treatment for giant cell tumor of bone is surgery, the editorialists point out. "If done thoroughly, the patient may be cured in up to 90% of cases."

But there are some cases of atypical giant cell tumor of bone with multiple local recurrences, multicentricity, pulmonary metastases, or lesions that are impossible to remove surgically without causing substantial morbidity, they continue.

"Surgery that causes major functional deficits is hardly justifiable for a lesion that is typically benign," but until now, promising alternatives have been lacking. "Hopefully, this will change," they write. "This excellent study . . . might change clinical practice in the treatment of complicated giant cell tumor of bone."

Denosumab is not currently marketed, although a launch is expected this year. It is awaiting approval for use in the treatment and prevention of postmenopausal osteoporosis, and for the prevention of bone loss in breast cancer patients receiving aromatase inhibitors and in prostate cancer patients receiving androgen-deprivation therapy. Another indication in late development is the treatment of bone metastases in patients with breast and prostate cancer. For most of these indications, the drug would be competing against bisphosphonates, but denosumab is a "first in its class" product — a monoclonal antibody directed against RANKL, a key mediator in bone turnover.

Majority of Patients Responded

The study was conducted by David Thomas, FRACP, PhD, from the Peter MacCallum Cancer Center in East Melbourne, Victoria, Australia, and colleagues in the United States and France, as well as researchers from Amgen, which funded the trial.

A total of 37 patients at 8 centers were enrolled, but 2 patients had insufficient histology or radiology data for efficacy assessment. All patients had recurrent or unresectable giant cell tumor of bone, and the most common sites for lesions were the pelvis, lungs, and lower extremities.

All patients were treated with denosumab 120 mg subcutaneously once a month (after loading doses on days 8 and 15 of the first month).

The primary end point was 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. This was seen in 30 of the 35 evaluable patients (86%), the researchers report.

Histology results were available for 20 patients, and all of these showed a complete or near complete elimination of giant cells. Radiologic results were available for 15 patients, and 10 of these showed a lack of progression or stable disease; in some cases, objective partial responses were observed. These observations correlate with reports of clinical benefit by the investigators, such as reductions in pain requiring less analgesia and improvements in function, mobility, and bone repair, Dr. Thomas and colleagues note.

Adverse events were reported by most patients (33 of 37), most frequently pain in an extremity (n = 7) or the back (n = 4) and headache (n = 4).

The results suggest that denosumab has "activity as a therapeutic agent" for giant cell tumor of bone, the researchers conclude.

Limitations of the current study are the fact that the sample size was small, the duration was short, and it was a single-group design, they note.

The small sample size and the heterogeneity of these patients "does not downgrade the results," according to the editorialists, "because the study population accurately represents patients with complications who are in need of additional systemic therapy."

But several issues remain to be addressed, including the mechanism of action involved and the duration of therapy needed, they explain. In 1 patient enrolled in the trial, tumor progression recurred after the drug was discontinued. "This raises the question of whether the inhibitory effect is only temporary and how long treatment must continue until a long-term or definitive effect is achieved," they write.

Prospective randomized trials with a high enrolment and a follow-up of at least 2 years will be necessary, they conclude.

The study was sponsored by Amgen, the manufacturer of denosumab. Dr. Thomas reports receiving consulting fees from Amgen and research grants from Novartis and Pfizer. Two of his coauthors report relationships with a variety of pharmaceutical companies, and 6 of his coauthors are employees of Amgen, as detailed in the paper. The editorialists have disclosed no relevant financial relationships.

Lancet Oncol. Published online February 10, 2010.