Expert Discusses Progress in Neuroendocrine Tumors

Jonathan Strosberg, MD

Treatment advances for patients with neuroendocrine tumors (NETs) are bringing hope to a therapeutic landscape that has seen little activity until recent years, says Jonathan Strosberg, MD.

OncLive: What does the current treatment landscape for NETs look like?

In an interview with OncLive, Strosberg, medical oncologist, Department of Gastrointestinal Oncology, section head, Neuroendocrine Division, chair, Gastrointestinal Department Research Program, Moffitt Cancer Center, discussed recent developments and emerging agents in the field of NETs.Strosberg: There have been substantial changes over the last decade—we have actually had 9 phase III clinical trials in the NET field, 7 of which have met their primary endpoint. This is against a backdrop of really no phase II trials until the 2000s. So, it has been an exciting decade to treat NETs.

Are there any significant ongoing trials?

We have been talking about trial results that have been reported in the last several years; these include the NETTER-1 study, which randomized patients to receive Lutathera with octreotide in patients with progressive midgut NETs. There is also the TELESTAR trial, which randomized patients with diarrhea related to carcinoid syndrome to receive telotristat (Xermelo) versus placebo and showed a significant improvement in diarrhea as well as reduction in urine 5-HIAA. Then there are the RADIANT trials, which prove the role of everolimus (Afinitor) in both pancreatic and non-pancreatic neuroendocrine tumors. As far as currently accruing clinical trials, I think there are several that are interesting. One is ECOG 2211, which is looking at temozolomide plus capecitabine versus temozolomide monotherapy in patients with progressive pancreatic NETs. It is a very exciting trial because there have been a lot of small retrospective studies, a few prospective studies looking at temozolomide-based combinations, but very little in terms of robust prospective clinical trials. This is going to be very important to help figure out if combinations are better than monotherapy.

We are looking forward to the results of pazopanib versus placebo in non-pancreatic NETs; if positive, this will be this first angiogenesis inhibitor to be used outside of pancreatic NETs—in other words, in carcinoid tumors.

There is an interesting trial that has not yet completed accrual that is looking at streptozocin chemotherapy versus everolimus in patients with pancreatic NETs, which is trying to get at the whole sequencing question.

What is the biggest challenge in treating neuroendocrine tumors?

And then there are some trials that are just starting out that are looking at immunotherapy, which really has not been well investigated in this field. Neuroendocrine tumors are extremely diverse. The first thing to figure out is which segment you are dealing with. We can categorize them in many different ways based on where they originate, their differentiation, grade, whether they are growing quickly or slowly, whether they are liver predominant or not, whether they express metastin receptors—so it is important to get all of the baseline clinical characteristics fully understood before coming up with a treatment plan.

How do you see the field progressing in the next 5 to 10 years?

We are learning more about the biology of the disease; mutations still do not have a lot of therapeutic implications, but that'll probably change.I think the most important trials are going to hopefully help us figure out how to best sequence treatments. Right now, there are a bunch of emerging therapies but really no information on how best to sequence them. These sequencing studies are just the start—perhaps they will give us some more information on how we should start sequencing treatments in the general population.

What do you hope community oncologists understand about the treatment landscape of NETs?

Everyone is interested in knowing which patients are most likely to benefit from immunotherapy. It is clear—at least with respect to well-differentiated NETs, where mutations are infrequent— that expression of PD-L1 is relatively low, so immunotherapy is not going to work for most patients. But, it may work for a small percentage of patents and we need to figure out who they are. My guess is patients who have had multiple lines of therapy, and, therefore, the possibility of having accumulated mutations over time rather than patients who have relatively unaggressive tumors early in their disease.I think the most important thing is to appreciate the rapidly expanding group of new and emerging treatment. We are not just talking about metastin analogs anymore or everolimus. And I am sure that most people have not heard of telotristat before—it is kind of a niche drug, but, certainly, if you have a patient with diarrhea and carcinoid syndrome, it is something that you should be aware of.