Treatment of neuroendocrine tumours with everolimus

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Published: 10 Nov 2010
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Dr Nicola Fazio - European Institute of Oncology, Milan, Italy

Dr Nicola Fazio speaks about the different types of neuroendocrine tumours and the results of the Radiant-2 and Radiant 3 trials which were presented at ESMO 2010. Radiant 2 compared everolimus and octreotide long-acting release (LAR) with placebo and octreotide LAR in patients with advanced neuroendocrine tumours while the Radiant 3 trial compared everolimus with a placebo in patients with advanced pancreatic neuroendocrine tumours (pNET).
Dr Fazio explains the mechanism of action of everolimus, the toxicities experienced by patients and discusses what conclusions can be made from the results of the Radiant trials.

ESMO 2010


Dr Nicola Fazio - European Institute of Oncology, Milan, Italy


Treatment of neuroendocrine tumours with everolimus


Interviewer, Peter Goodwin 


You’ve been listening to some extremely interesting studies this morning, that in fact you had a part in the investigation of: Radiant 1 and Radiant 2. I want to ask you about them, they’re about neuroendocrine tumours. But first, can you give me the background on what have been the problems in these areas, and which tumours particularly are we talking about?


Yes, this is an important meeting, because the two phase III trials, with a high number of patients with neuroendocrine tumour were presented with Radiant 2 and Radiant 3. For Radiant 2 it was the first time to be presented, instead for Radiant 3 it’s the second time, because, if I remember well, in the Barcelona gastro-intestinal meeting, it was already presented.


The background is that we have two particular settings of neuroendocrine tumours: the pancreatic ones, where in some countries chemotherapy is even proposed, the progressing pancreatic advancing neuroendocrine tumours that in the Radiant 3 trial were treated with everolimus versus placebo. The other setting is the functioning neuroendocrine tumours that are the tumours with a clinical syndrome relating to one or more substances produced by the tumour. In that case everolimus plus octreotide long-acting release was compared with octreotide placebo. In both the studies the tumours were progressing at baseline.


Could you distinguish for me between what is called a functioning neuroendocrine tumour and a secreting neuroendocrine tumour? Could you just clear up exactly what we’re talking about here?


Yes, neuroendocrine tumours could be totally silent, totally asymptomatic. You can find the tumour incidentally in several cases. In that situation we call them non-functioning tumours because there is not any clinical syndrome. The most known clinical syndrome is the combination of flushing and diarrhoea which we call the carcinoid syndrome. Anyway, neuroendocrine tumours can produce several hormones and several substances even without any clinical syndrome, in that case we call them secreting tumours, but not necessarily functioning tumours.


Now let’s look at the study from the MD Anderson Cancer Centre in Houston, the Radiant 2, which was using everolimus and octreotide in functioning neuroendocrine tumours. What did we hear about this morning?


So, this morning I heard that the results in terms of progression free survival, that was the main endpoint of the study, were not statistically significant, because the proclaimed hazard ratio was not reached for a very little bit of difference. But in any case, the difference in clinical terms was clear because the group treated with everolimus had a longer progression free survival than the other group.


What was the thinking behind adding everolimus to the standard octreotide?


I think that this study is clinically positive, even though statistically negative.


And in theory, why would it be good to use everolimus?


Yes, because if I had a patient with a functioning neuroendocrine tumour progressing, for example, to octreotide, I would use everolimus in order to stop the progression based on the clinical results of this study.


Right. Now there was another study, Radiant 3, looking at pancreatic neuroendocrine tumours. What was presented there?


Yes, we already knew the results of this study, but in this case we have a clear statistical advantage for everolimus, in favour of everolimus compared with a placebo. Because in neuroendocrine tumours, and also in pancreatic ones, we don’t have a standard treatment so the control arm was a placebo arm. Everolimus prolonged the progression-free survival to 11 months compared to 4.6 months for the placebo arm so it was statistically and clinically significant in my opinion.


What category of patients were being looked at?


These are patients with tumour progressing, radiologically progressing, so you have a tumour with a clear evolution at the CT scan and MRI. So they are tumours that are potentially aggressive neuroendocrine tumours, tumours that in some countries are treated with chemotherapy, for example.


Could you explain some of the mechanisms of everolimus which would help to explain the clinical benefits that were observed, both in the Radiant 2 and the Radiant 3 studies?


Yes, everolimus is an mTOR inhibitor and mTOR is a good target but is a metabolic target, even in the normal cells, and everolimus inhibits mTOR specifically. And we know that mTOR is activated in many neuroendocrine tumours. The problem is that, as in other pathways, the mTOR pathway could have several mechanisms of resistance because the downstream and upstream elements of that pathway can reactivate the mTOR itself. So, for example, one potential strong rationale in neuroendocrine tumours is the combination of everolimus and octreotide because octreotide is known to inhibit the IGF1 pathway, and the AKT, these are two of the supposed mechanisms of resistance to mTOR inhibition so a combination of everolimus and octreotide could be synergistic.


You are of course treating patients who are very ill. What about the toxicities of adding an additional agent?


I think that everolimus is a relatively well-tolerated drug. We already knew it because it is used in post-transplant patients to inhibit rejection. And so we have data for several years. But also in neuroendocrine tumours where patients are treated for more than three years, for example, the main toxicity is the stomatitis, the after stomatitis, and then diarrhoea and then a particular toxicity that is a known infective of pneumonitis. But all of them can be relatively well-managed, for example reducing the dose of the drug; 10mg is the dose normally but also at 5mg per day continuously the drug could be active and well tolerated. So I think that they are relatively well-managed toxicities.


So for you, from the data so far both in pancreatic and in the advanced neuroendocrine tumours, the functioning tumours, the clinical benefit is worth having. What do you think about overall survival, the possibility of extending survival in these?


Yes, both trials, if I remember well, had a crossover. So in neuroendocrine tumours it is difficult to evaluate the overall survival because in many cases the patients could have a lucky long survival, so they receive a lot of treatment so it’s difficult to have, with the relatively short follow-up, the data about survival. But specifically in these two studies, there was also the crossover phenomenon so although survival is not significant in the Radiant 3 for example, not different in Radiant 3, but it’s obvious.


So what you’re saying is that the drug becomes so attractive that everybody takes it and in the end you can’t even measure survival?


The drug is surely active about the clinical benefit, and surely effective in Radiant 3, we have data about efficacy. We know that it can be in action even late action. So, for example, we observed partial responses after one year of treatment that were totally different from other drugs and in particular from chemotherapy.


So with the incomplete evidence on overall survival, but nevertheless the strong evidence on clinical benefit, what would you say to doctors at this point, who have patients to treat?


I would say that this drug of course now is not yet approved, but I think that the FDA will approve this drug in the pancreatic neuroendocrine tumours in advanced stage and progressing at baseline. I think that it’s justified in clinical practice to consider this drug, specifically for pancreatic neuroendocrine tumours but also for progressing functioning intestinal neuroendocrine tumours, when they progress to octreotide.


Well Nicola thank you very much for joining us on, it’s been great seeing you here and I hope we have the chance to catch up again soon.