O'Neil Shares Insight on Growing Therapeutic Arsenal for GI Tract NETs

Bert O’Neil, MD

Physicians have another means of treatment following the FDA approval of Lutathera (lutetium Lu 177 dotate) in January 2018 for patients with somatostatin receptor—positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

The approval garnered great excitement; however, Bert H. O’Neil, MD, said that though the treatment is going to be a “game changer” for patients with receptor-positive disease, Lutathera should be reserved for those who progress on a somatostatin analog.

The approval was based on the phase III results of the NETTER-1 trial, in which the agent was compared with high-dose octreotide LAR (Sandostatin). Patients with 1 or 2 midgut NETs who had progressed on 30 mg of octreotide were randomized to Lutathera (n = 116) or octreotide (n = 113). They received 4 doses of Lutathera at 7.4 GBq every 8 weeks in combination with 30 mg of octreotide or 60 mg of octreotide LAR every 4 weeks.

The combination induced a 79% reduction in the risk of progression or death. At an updated survival analysis at the 2018 ASCO Annual Meeting, the median OS was 27.4 months in the octreotide arm and was not reached in those who received Lutathera. Moreover, there were 30 progression-free survival (PFS) events in the Lutathera arm and 78 in the octreotide arm (HR, 0.21; 95% CI, 0.14-0.33; P <.0001).

Another approval may be on the horizon following the FDA’s priority review of a version of the radiopharmaceutical iobenguane I-131 (Azedra) for patients with malignant or recurrent pheochromocytoma or paraganglioma.

In the interim, physicians continue to cultivate and refine their approaches with targeted therapies, such as everolimus (Afinitor) and sunitinib (Sutent), O’Neil explained.

OncLive: What has been developing in the NETs space?

How do treatments vary across NET subtypes?

Is Lutathera now the predominant treatment for GEP-NETs?

Can you speak to the activity of capecitabine and temozolomide?

What is your approach in selecting targeted therapies?

What’s an area of research you would like to see addressed?

Can you elaborate on those trials?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, O’Neil, the Joseph W. and Jackie J. Cusick Professor of Oncology, professor of medicine, and director of the Phase I and Gastrointestinal Oncology Programs at Indiana University, discussed the prevalence of NETs and the agents that are used to treat patients who present with them.O’Neil: NETs are sort of a surprisingly common group of tumors. They’re thought of as rare, but there are a lot of patients out there with these diseases because they tend to live a long time. We’re seeing some interesting evolution of treatment options. We have gone from a period where all we really had was either chemotherapy or the somatostatin analogue octreotide to now having other somatostatin analogs, such as lanreotide (Somatuline Depot), pasireotide (Signifor), and other targeted agents that have shown efficacy. Perhaps most excitingly is the recent approval of what’s called peptide-receptor radionuclide therapy (PRRT), which is really going to be a game changer for a lot of our patients. This is a nuclear medicine—based therapy that utilizes a radio-labeled octreotide-like molecule or somatostatin analogue that can deliver radiotherapy all over the body to where the tumors are.When you’re talking about di erentiating NETs of the gastrointestinal tract, the most important distinction is to think about those that arise in the pancreas versus other areas for a number of reasons. The tumors that arise in the pancreas have a wide variety of potential hormone-associated syndromes that are distinct from carcinoid syndrome, which tends to occur in small bowel NETs. The other important difference between the 2 types is their response to therapy. Pancreatic tumors are more likely to have radiographic response to some of our targeted therapies and traditional chemotherapeutic agents, but on the flip side, they tend to have somewhat more aggressive behavior than a lot of the small bowel NETs.For patients who progress on a somatostatin analogue which is still the type of treatment that’s changed the lifespan of these patients—especially if they have carcinoid syndrome—then PRRT is going to be the next therapy of choice for the majority of these patients. That is assuming they have receptor-positive tumors.Capecitabine and temozolomide is a good regimen, particularly for [patients with] pancreatic NETs. For low-grade, small bowel, or other carcinoid tumors, you don’t see a lot of responses [with that treatment]. You’re definitely going to see more responses in the pancreatic tumors. It’s a good option for someone with a pancreatic NET who needs a response. I would put it behind other options for small bowel NETs.Unfortunately, our choices still aren’t tremendously large. For the most part, beyond initial treatment with a somatostatin analog, we’re choosing between everolimus and sunitinib. They have shown similar efficacy in spite of having relatively different mechanisms of action. A lot of us choose an agent based on tolerability. I’ve tended to go with everolimus as my first-line therapy, especially in those patients with pancreatic NETs and following the data from RADIANT-4, also in small bowel NETs.Sequencing is important, even now. How do we best sequence these therapies? We don’t really know how to incorporate chemotherapy with the targeted therapies. Which one should be first and in which patients? We still need new targets in this disease. We’ll need to understand if we can do combination therapy with PRRT and if there’s any potential to synergize there. Finally, what patients, if any, are going to respond to immunotherapy?There was a small study with pembrolizumab (Keytruda) that we were a part of. It was part of the KEYNOTE program with multiple tumor types, and we saw some patients with partial responses. There was evidence of response, although not a lot of patients responded. A lot of patients had stable disease, but sometimes that’s hard to interpret in this particular patient population where stable disease for periods of time is the norm.

Strosberg JR, Wolin EM, Chasen B, et al. First update on overall survival, progres- sion-free survival, and health-related time-to-deterioration quality of life from the NETTER-1 study: 177Lu-Dotatate vs. high dose octreotide in progressive midgut neuroendocrine tumors. J Clin Oncol. 2018;36 (suppl; abstr 4099).