Today we presented very exciting results of a phase II trial. For a phase II trial the enrolment was huge, more than 500 patients in a rare condition. It’s called giant cell tumour of bone. It’s a good and bad disease because it’s biologically benign so less aggressive as compared to a high grade tumour but it can disrupt the bone so cause lots of limitations for quality of life and in some cases also gives lung metastases. So for the advanced cases until a few years ago the only option was surgery and surgery not only has a high morbidity in the bone but also the relapse rate is as high as 50% in some of the serious. So the trial we presented today is on the use of a monoclonal antibody, it’s called denosumab, direct rank ligand. Rank ligand is expressed by stromal cells and activates the osteoclast differentiation, immature osteoclasts. So it causes eventually increased bone erosion. Denosumab has been approved for the treatment of bone metastases and since 2013 for the treatment of giant cell tumour of bone.
The results presented today were on the long-term efficacy on giant cell tumour of bone and it’s a pretty new study because for bone metastases denosumab was used only for three years; in this trial we had patients treated for up to 7-8 years. The drug was able to control the disease in almost all advanced metastatic patients undergoing treatment continuously and there was also a cohort of patients doing the drug neoadjuvant and then undergoing resection. In those patients we observed relapse rates of 34% after interruption but denosumab rechallenge was also able to control the disease. Importantly, 37% of the patients in the surgical cohort eventually ended to be treated by denosumab monotherapy. So coming from an orthopaedic high grade sarcoma tumour centre I have never seen a drug so targeted and so active on almost all tumours when given continuously.
When we stop the drug we have to be careful of potential progression of the disease in a proportion of the patients. Also the side effects of this drug were really manageable. In the first place it’s a subcutaneous drug given once a month. The most important side effect is osteonecrosis of the jaw which was also observed in the Zometa trial. We found confirmed ONJ in 28 patients in the study, so about 5.3%. This data suggests careful prevention of this side effect because most of the patients with ONJ had prior tooth extraction or infection before the ONJ event. So it also reflects the length of the study, the study started running in 2006 and now we are more aware of the potential problem linked to bad oral cavity care. So that’s really the point from the inclusion of the patients, so we should select patients also based on these comorbidities as known now and also following during treatment.
What were the measures in assessing quality of life?
The pain but also, yes, from the surgery. For example, I have a patient, he started the treatment when he was 53 years old. He worked in the nightlife, was a very active guy, and he had a pelvic giant cell tumour of bone. So he underwent surgery in the past and then relapsed so we put him to neoadjuvant denosumab. He did very well on treatment and then he underwent a second operation, so he was off treatment for some point. Then he relapsed, he received a second surgery and then after that relapsed again. So eventually we decided to keep him on denosumab and now he has his job, his girlfriend, his active life and he’s not due surgical operations any longer. So if the patient is young the ONJ problems are usually not a concern and, as I told, the drug is really easy to use, subcutaneous injection, and able to keep controlling the disease for also years.
Was quality of life one of the endpoints for the trial?
The first endpoint was safety and quality of life was not the primary endpoint. But, yes, the progression free survival was one of the endpoints. Usually progression in the bone lesion is associated with decreased quality of life because they can’t walk sometimes.
And overall survival?
No, the overall survival wasn’t the endpoint of the study but it’s almost 100% because the progression free survival at five years is 88%, so almost reaching 90%. This figure might even look better because the diagnosis of giant cell tumour of the bone is usually unequivocal but sometimes in this trial we found sampling errors, which means that in some cases progression was reviewed and we found high grade sarcoma put by mistake in the trial. So I think the overall survival at five years is 100%.
Is there anyone for whom you would not recommend denosumab?
That decision should be shared with the orthopaedic surgeon. So in the case of a small lesion that they can easily curate, those might be the cases that I would leave to the surgeon. So very small initial stage disease that the surgeon judges curable by small curettage, in size, of course, not too difficult to handle by their own point of view. Anything else, yes, because of the safety and also of the incredible activity which reflects that we really get to the target; the RANK ligand in this disease is a key pathway.