Expert Discusses Promising Results for Denosumab in Patients With Bone Tumors

Emanuela Palmerini, MD

Emanuela Palmerini, MD

In a recent open-label phase II study, denosumab (Xgeva) demonstrated favorable results in patients with resectable giant cell tumor of bone (GCTB). More than one-third of the trial patients avoided surgery and nearly half had less morbidity with surgery when treated with denosumab.

The study was designed to evaluate the safety and efficacy of denosumab in patients with resectable and nonresectable GCTB. Investigators at 27 international sites enrolled of total of 532 patients.

“This drug was able to control the disease in all patients with metastases or unresectable tumors and, in addition, in patients with resectable tumors, the drug was able to downstage the surgical indication,” said lead study author Emanuela Palmerini, MD.

In an interview withTargeted Oncology, Palmerini, Istituto Ortopedico Rizzoli, discussed the efficacy of denosumab in patients with resectable and unresectable GCTB, a historically benign condition.

Targeted Oncology: Can you start by discussing the main findings of the study?

Palmerini:We presented an exciting phase II study enrolling more than 500 patients with a rare condition known as GCTB. It is a tumor that is aggressive, which might metastasize in some cases. Traditionally, it was cured by surgery alone, but the relapse rate was up to 50% in some cases and it really affected quality of life.

The study uses a monoclonal antibody, denosumab, direct to RANK-Ligand, which is constituently expressed by stromal cells within the tumor. This drug was able to control the disease in all patients with metastases or unresectable tumors and, in addition, in patients with resectable tumors, the drug was able to downstage the surgical indication. This means that patients that were meant to have a resection then received a curettage, which is a much less invasive operation.

There are some side effects to take into account. The major side effect is osteonecrosis of the jaw (ONJ), but it was mainly associated with tooth extraction. One key message from the study is that patients with this condition that take the drug for a long period of time should be instructed to have a hygienic procedure and to receive dental checks routinely during treatment.

Targeted Oncology: In terms of adverse events, denosumab is commonly used to treat bone metastasis. In this case, is it given at a different dose?

Palmerini:Yes, this is a very interesting question, because this is the first study using the same drug used for osteoporosis and bone metastasis. The dose is 120 mg, which is the same as bone metastasis and is much higher compared to osteoporosis. Usually, we have data on bone metastasis of up to 3 years. In this trial, the patients were treated because of the tumor and the incurable metastatic disease, for more than 7 years in some cases. As a result, there were no data on safety for that period of time. Thus, we can confirm that the drug can be given at 120 mg per month for a longer exposure with some risk.

Also, we observed hypercalcemia in 4 cases after drug interruption. When we decide, for any reason, to interrupt the trial, the patient should be aware to follow up with their treating physician. Overall, it is a very important drug, which will positively affect the management of this rare condition.

Targeted Oncology: This is a relatively new treatment in a space where there have not been many treatment options for quite some time. Which patients would you select for this treatment and how would you sequence it along with surgery?

Palmerini:The patients that would benefit the most from this treatment are, for example, those with a larger tumor of the pelvis. There is a case of a 70-year-old man who had a lesion going from the spine to the left iliac wing. There is no cure for that, and we know that radiation therapy cannot be the treatment because of radiation-induced sarcoma. So, for example, this patient underwent 4 years of denosumab alone with some dental issues, but now he is 4 years off trial and is cured and back to his home bike everyday. The ideal patient is one with advanced GCTB.

For the patients with smaller tumors or one that can be managed by a surgeon, we should be very careful, because denosumab transforms the lesions and a surgeon can sometimes perform under optimal treatment after neoadjuvant denosumab. In a neoadjuvant indication, I think that we have to learn not only how to select patients, but also how to plan surgical procedures carefully. There are data in this trial that might be very helpful for our surgeons as well.

Targeted Oncology: What are the next steps with denosumab?

Palmerini:These diseases are rare, but there are different studies we would like to pursue in order to make better use of the drug. We will look at different schedules in the next few months.

Targeted Oncology: Is there anything else you would like to highlight about this study?

Palmerini:I am enthusiastic, because I am a bone sarcoma medical oncologist, so I usually treat high-grade tumors, and our curves are depressing. This study just confirms that when you find the key target and RANK-Ligand is really responsible for bone erosion, the results come along.