Dr. Nicola Fazio explains the findings of the RADIANT-4 Trial and discusses mTOR inhibition in neuroendocrine tumors.
FILMED AT THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY (ASCO) ANNUAL MEETING, JUNE 2016
CAN YOU TELL US ABOUT THE FINDINGS OF THE RADIANT-4 TRIAL?
00:09 – The RADIANT-4 trial was an important trial covering two settings of populations that are lung and gastrointestinal NET non-functioning populations. And it was important because it was evidence of efficacy of everolimus 10 mg per day compared with a placebo in these two populations where before we didn’t have any standard therapy. Therefore, now FDA approved, but also a few days ago even EMA approved everolimus as being recognised as a possible therapeutic option in advanced NET from gastrointestinal and lung. Of course, we mean while differentiated NET, not high-grade NET, but specifically non-pancreatic and non-functioning.
WHAT COMBINATION REGIMENS ARE BEING INVESTIGATED IN NETS?
01:18 – Many combinations are under investigation in NETs considering all types of NETs. Specifically, we are studying a combination of PI3K inhibitors and mTOR inhibitors in order to reverse the resistance to mTOR inhibitors. For example, in pancreatic NETs we are studying a combination of BYL719 that is a selective inhibitor of PI3K combined with everolimus and phase I B trial in pancreatic NET is ongoing all over the world. That’s an important setting to be investigating considering that these combination seems to be more tolerated than previous one. For example, BC235 that was a specific inhibitor of PI3K but also an inhibitor of mTORC1 and mTORC2. We investigated in the past this drug but it resulted not manageable in terms of clinical management. Therefore, it was not possible to go ahead with that investigation programme. Therefore, now these PI3K inhibitors is one of the most important setting in investigation in NETs.
ARE THERE ANY PREDICTORS OF RESPONSE TO MTOR INHIBITORS IN NETS?
02:59 – That is a negative point in NET field since so far we don’t have any validated predictive factor, really predictive of efficacy of any therapy. There are several reports indicating that we could have, for example, prediction to everolimus efficacy with phosphor related mTOR, or phosphor related P70 S6 kinase. But no prospective trial validating that has been published so far. Some ones is moving from monoanalytes so called to the multianalyte evaluating simultaneously many potential predictive factors. For example, also in this ASCO meeting there is some poster indicating that the so-called NET test that is a combination of 50 transcripts and that is a blood test, can predict the efficacy of PRRT.
WHAT OTHER THERAPEUTIC STRATEGIES ARE CURRENTLY UNDER INVESTIGATION?
04:13 – In NET there are several strategies under investigation so far, not necessarily single therapy trials. There are a lot of biological agents under investigation in phase II and phase III trials, but there are also different strategies trial, for example sequencing trial. There is a trial ongoing in Europe comparing the sequence everolimus followed by chemotherapy versus the opposite sequence, or some trial evaluating the combination of PRRT with other biologic agents or even chemotherapy. But NET field is peculiar compared with other fields, oncological fields, since even other types of therapy, including liver-directed therapies, for example intervention radiological procedures or even surgical approach on the primary tumour and on the metastasis can be included in some strategies of NET therapy. Therefore, it’s difficult in NET to perform trial comparing different strategies to each other.