Targeted Therapies for the Treatment of NETs

Simron Singh, MD: Sure. For our audience, everolimus is an oral agent. It’s an mTOR [mechanistic target of rapamycin] inhibitor. It’s a daily dose that’s taken, as I mentioned, orally. It’s probably the most studied targeted agent we have in the neuroendocrine tumor field today. There have been numerous, large randomized controlled trials showing its efficacy. The first one was the RADIANT-3 study specifically in pancreatic neuroendocrine tumors. This study showed a significant benefit in progression-free survival for patients with pancreatic neuroendocrine tumors who were taking everolimus. Subsequently, there was the RADIANT-4 study, which really looked at the entire gastrointestinal subgroup as well as the lung neuroendocrine subgroup. This study showed an advantage. This led everolimus becoming the only approved therapy for lung neuroendocrine cancers. As opposed to gastrointestinal and pancreas NETs, where we have other options, our only approved option at this time is everolimus.

It is an oral agent, so that offers a bit of patient convenience, but it does have toxicities that need to be managed—things like mucositis, some mild fatigue, and diarrhea. There are some endocrine abnormalities including hyperglycemia. We’ve got to watch a patient’s cholesterol and lipids. There are rare adverse effects as well, such as fibrosis in the lungs, which need to be monitored. So it does require monitoring. However, the toxicities can be managed. We have to ensure that we’re active participants in that care.

Jonathan R. Strosberg, MD: Right. I think it’s important to also consider the differences in populations and outcomes of RADIANT-2 versus RADIANT-4. RADIANT-2, of course, was a randomized study of octreotide plus everolimus versus octreotide plus placebo in patients with neuroendocrine tumors and history of carcinoid syndrome. So it was mostly a study of fairly typical midgut neuroendocrine tumors, although there were some non-midgut tumors as well. The study fell short of statistical significance. And, of course, even on the placebo in this relatively indolent population, the median progression-free survival was quite long. RADIANT-4 looked at nonfunctioning tumors. It required a relatively short interval at which time they had to have disease progression. So it turned out to be a much more aggressive population with a median progression-free survival of only 4 months on placebo. This turned out to be a really positive study.

My personal take-home message from that would be that everolimus is probably more appropriate for your relatively aggressive, non-midgut NETs rather than midgut NETs. I wonder whether you have the same conclusion, or whether it’s more of a nonfunctioning versus functioning thing, or aggressive versus indolent? How do you see that?

Simron Singh, MD: It’s interesting. I probably disagree with you slightly on your interpretation. When we looked at RADIANT-2, there were a number of factors that were involved. That was early on. This was one of the first randomized trials we ever did in neuroendocrine cancer. In this heterogeneous population, we were really learning how to do randomized trials. As you know, there was imbalance between the arms. I think having a placebo arm that received somatostatin analogs, realizing that we now know that there is probably an antiproliferative effect, maybe also diluted the effect that we saw. And, as you mentioned, it was very close to being positive. So to be quite honest, I realize that we have a negative study in RADIANT-2, but I find that everolimus is probably going to be effective for most neuroendocrine cancers. Certainly for lung patients, we have few other options.

Jonathan R. Strosberg, MD: Right.

Simron Singh, MD: Regarding your comment about the midgut NETs, I think it’s probably correct when we look at the analysis from the gastrointestinal subgroup. I would certainly start with somatostatin analogs. And with the recent introduction of PRRT [peptide receptor radionuclide therapy], I think we have a number of different options that we want to consider. But I think it’s definitely part of our armamentarium, even in midgut tumors.

Jonathan R. Strosberg, MD: And, of course it’s important to select patients appropriately.

Simron Singh, MD: Yes, and take patient preference into account as well.

Jonathan R. Strosberg, MD: How about sunitinib [Sutent]? For whom do you use that?

Simron Singh, MD: We have a lot less data for sunitinib, but we do have good data in the metastatic pancreatic neuroendocrine tumor population that says that it is very similar to everolimus. We know that, in fact, it’s another oral agent that has a good effect in those patients with pancreatic neuroendocrine tumors. Again, we have to understand toxicities. It can cause a bit more fatigue. It can cause some hypertension.

Jonathan R. Strosberg, MD: And hand-foot syndrome.

Simron Singh, MD: And hand-foot syndrome, absolutely. So I think it’s important that we sort of tailor our decision to use everolimus with sunitinib in our pancreas patients. We need to try to give the right treatment to the right patient.

Jonathan R. Strosberg, MD: Yes. It’s really striking how similar the randomized phase III Sutent trial was to RADIANT-3. As far as median progression-free survival, we saw that it basically doubled—from about 4 or 5 months on placebo to about 10 or 11 months with treatment. So the outcomes were very, very similar. Sometimes we can use comorbidities to help choose between sunitinib and everolimus. So for patients with diabetes, for example, you may want to consider Sutent. For patients who have a history of cardiovascular disease, or hypertension, or bleeding diathesis, you may want to consider everolimus.

Transcript edited for clarity.