NETs Management: Unmet Needs and Future Direction

Pamela Kunz, MD: There are still many unmet needs in the field of NET [neuroendocrine tumor] research. As I mentioned before, we are fortunate to now have a number of treatments available for patients. One of the unmet needs is determining the optimal sequence of therapies. There are some ongoing studies trying to evaluate that, especially on the international level, looking at sequencing of chemotherapy versus biologics versus PRRT, and we’re eagerly awaiting the results of some of those studies.

In addition, PRRT [peptide receptor radionuclide treatment] has been a game-changer in this disease, and we’re eager to look at how to optimize PRRT, whether that is minimizing adverse effects, making it more effective, or applying it to other, less common NETs. For example, there are some upcoming studies looking at 177Lu-DOTATATE in patients with paraganglioma and pheochromocytoma, and also in lung neuroendocrine tumors, which was not included in the FDA indication approved 2 years ago. We’re also looking at using other radio peptides— somatostatin receptor agonists, as opposed to antagonists—so there are a number of different ways of looking at PRRT, which is exciting.

In addition, there are also agents that can take advantage of the somatostatin receptor itself. Looking at it by specific antibodies or antibody drug conjugates, somatostatin receptors are really 1 of the perfect targets because they are very specific to neuroendocrine tumors. There are a number of companies looking at other ways to take advantage of that specific target. I’m eager to also see further work in immunotherapy in neuroendocrine tumors.

NETs, to date, have proven to be not particularly responsive to immunotherapies, and I’m speaking specifically of the well-differentiated grade 1 and 2 neuroendocrine tumors. They tend to have a very low mutation burden, and single-agent checkpoint inhibitors have not been particularly effective. There are a lot of questions around how we can change NETs, which tend not to be a very immuno-responsive tumor type, into 1 that could be. Are there ways to use combination therapies that might turn NETs into an immuno-response tumor?

Grade 3 neuroendocrine tumors are also an unmet need. There’s an ongoing clinical trial through the ECOG-ACRIN Cancer Research Group that’s looking at platinum etoposide versus temozolomide and capecitabine in grade 3 neuroendocrine neoplasms. In addition, immunotherapy may play a special role in that subset of neuroendocrine neoplasms because it may have a higher tumor mutation burden, so there are some ongoing studies that will likely evaluate immunotherapy in grade 3 neuroendocrine neoplasms.

I’m really eager to see what the next 5 years will look like for NET research. We’ve accomplished quite a bit in the last decade, and it’s really interesting to reflect back on that period of time. Prior to the early or mid-2000s when we started having some new FDA approvals, NETs were considered so rare that they were not worthy of doing large phase 3 clinical trials, or rare enough that we couldn’t accrue patients to these trials.

What the last decade of research has shown is that it is, in fact, a disease worth studying. We can enroll patients on these studies, and NETs are actually not as rare as we think. Because patients with grade 1 and 2 NETs often have a more indolent disease course and live for a long time, it means they are more prevalent than some more common cancers like gastric adenocarcinoma and pancreatic adenocarcinoma.

Though the incidence is low, meaning the number diagnosed per year, the prevalence—or the number of patients living currently with NETs—is quite high. It means that we need to engage more young researchers in the field. We need to train community oncologists how to take care of these patients because they will encounter them in their practice. I’m eager to see the next generation of clinical trials, and I really think they will include more evaluations of PRRT and more novel therapies.

Transcript Edited for Clarity