35th ESMO Congress, 8–12 October 2010, Milan

Interview with Professor Allan Lipton (Hershey Medical Center, Pennsylvania, USA)

Denosumab treatment of skeletal related events

The study we’ve been looking at is addressing a terribly important problem in cancer patients. This year in my country, in the United States, there will be about 400,000 new patients with bone metastasis so this is a huge problem and these people are prone to have skeletal events which are a fracture, radiation therapy, surgery to bone, spinal cord compression, hypercalcaemia. But the standard of treatment for the last decade has been to treat people with established bone metastasis with zoledronic acid or Zometa.

In the study that we presented today we’re looking at a new drug for bone metastasis called Denosumab. Denosumab is an antibody to a molecule called RANK ligand, which is the molecule that stimulates osteoclasts.

So this is a different approach from using bisphosphonate in this role?

It’s a different class of drugs, it’s not a bisphosphonate and it’s a specific inhibitor of what turns on the osteoclast. The osteoclast is turned on by this molecule, RANK ligand, so this is a specific targeted inhibition of osteoclast maturation and function.

So hopefully it’s going to be more specific. What did you do in the study?

Well there were three studies that were performed, all three studies had the same design. They took patients with metastatic cancer to bone, one study was breast cancer, second study was prostate cancer, third study was lung cancer and other solid tumours. So three different studies in each disease type and they all had the same design – patients were randomised to either monthly zoledronic acid, the standard therapy, or monthly Denosumab, the new drug, 120mg a month; comparing monthly old drug to monthly new drug and looking at end results and looking at events and survival and progression.

Now actually there were three individual studies and you have now pooled the results to get a very large number of patients covered.

Right, the abstract that we just presented at ESMO was pooling the three studies to give us almost 5,500 patients, which is a huge reservoir of information. And in these 5,500 patients we were able to look at different subsets to compare the drug in different subsets of patients.

And what have you found?

Well we found that the results were quite consistent in each study. There was about a 17% decrease in events in each study, we knew that from the individual studies and when we pooled the studies we learned that individual skeletal events are significantly decreased. So there’s a significant decrease in fractures; there’s a significant decrease in the need for radiation therapy with Denosumab compared to Zometa and there’s a very strong trend in decreasing spinal cord compression and decreasing the need for surgery.

We also found that patients who had an increase in their pain was less with the new drug compared to the old drug. We found that the increase in narcotics was less with the new drug compared to the old drug and the quality of life was maintained at a better level with Denosumab compared to zoledronic acid. So this pooling of patients into this 5,500 patient reservoir allowed us to look at each of these different endpoints.

Now in day-to-day practical terms with your patients, how much practical difference is this going to make if you were to adopt the new agent?

Well it makes a big practical difference. It’s a 20% decrease in events occurring so there’s a 20% decrease that you’re going to have a fracture, a 20% decrease that you’re going to have the need for radiation therapy. These are big differences, these are as large as the differences of a generation ago when zoledronic acid was compared to iridium and these benefits are achieved without renal toxicity.

Without renal toxicity but what about other toxicities, these targeted agents do sometimes have them?

Yes they do. With zoledronic acid there are more acute phase reactions – fever, chills, arthralgia soon after starting the drug than there is with Denosumab, it has fewer acute phase reactions. There is more asymptomatic hypocalcaemia with Denosumab than zoledronic acid and it was of great interest to look at the incidence of osteonecrosis of the jaw, ONJ. The incidence of ONJ is very low in both arms and it’s balanced so there was the hope at one time that Denosumab might not cause ONJ but it does at about the same rate that Zometa does. We’ve learned that the true incidence of ONJ in patients treated with bisphosphonate is about 0.5% a year. So a prospective study carefully looking at the jaw bone has really taught us what the incidence is and much lower than one had seen in the literature prior to that time.

So what brief summary would you leave doctors with?

Well the brief summary is that we have a new drug that will shortly be approved both in Europe and in the United States to treat patients with bone metastasis, which can improve the outcomes by almost 20% in terms of decreasing events, so it’s a major step forward.

Well, Allan, it’s been a great pleasure meeting you here in Milan and I hope to see you back in Pennsylvania some time.