The SPLENDOUR trial is an academic trial starting from a hypothesis generating dataset which was presented some years ago. This dataset consists in a trial which was using denosumab to protect the bone, to avoid or to stay away from skeletal related events in a trial in patients with bone mets. In this big trial the subgroup of lung cancer patients were extracting benefit from denosumab in terms of bone protection but they were also getting a better survival. So the hypothesis is beyond the bone maybe this pathway that you inhibit, which is the NF-kappa B pathway, might have an anti-tumour effect. So the hypothesis is is denosumab a potential anti-cancer drug?

So we just randomised patients between chemo plus denosumab versus chemo front line with the idea that denosumab can be continued as long as tolerated over time. The primary endpoint survival, very clean and very straight to the point. We unfortunately had to close the trial before the end because of the environment of immunotherapy so chemo was not any more the front line strategy and there were too many competitive trials going around. But we did recruit more than 500 patients which is not a small trial.

I was telling yesterday, I don’t think that the problem of this trial is that it is underpowered, the problem of this trial is it’s purely negative. You shouldn’t try to find a reason why. The curves are completely superimposed, there is no signal of improvement of outcome, whichever outcome, in patients with or without bone mets with denosumab. So that’s where we are.

We still have some biomarker assessments, maybe the expression of the RANK ligand or the receptors, the RANK receptor, might describe a population of patients who benefit a little bit of benefit but it would be a subgroup. So our question, should you give denosumab to all your patients? The answer is no, definitely not. Sometimes it happens – this was a negative negative trial.