Expert Shares Insight on Navigating Neuroendocrine Tumor Treatment

Paul R. Helft, MD

Since the FDA approval of Lutathera (lutetium Lu 177 dotatate) in January 2018, other treatments may take a backseat to peptide receptor radionuclide therapy (PRRT) for patients with gastroenteropancreatic (GEP)-neuroendocrine tumors (NETs), says Paul R. Helft, MD. The reason is that because Lutathera can concurrently treat multiple sites of disease, it could be the dominant therapy in this space.

The approval was based on results from the phase III NETTER-1 trial, which showed a 79% reduction in the risk of progression or death with Lutathera compared with octreotide (Sandostatin) in patients with midgut NETs. The overall response rate with Lutathera was 13% versus 4% with octreotide (P <.0148). The overall survival interim analysis showed a 48% reduction in the risk of death with Lutathera versus octreotide (HR, 0.52; 95% CI, 0.32-0.84).

Moreover, findings of small studies have confirmed the efficacy of combination therapy with capecitabine (Xeloda) and temozolomide (Temodar) as well. But regarding progress with immunotherapy, Helft said that well-differentiated NETs have a fairly quiet genome, adding, “The basic markers that immunotherapy has demonstrated efficacy in are absent in GEP-NETs.”

OncLive: Can you provide an overview of your presentation on NETs?

Is there a subset of NETs that is more difficult to treat than other subtypes?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Helft, professor of medicine, Indiana University School of Medicine, Indiana University Melvin and Bren Simon Cancer Center, discussed the incidence of gastrointestinal (GI) NETs and available and emerging treatment methods.Helft: NETs are a group of tumors that can originate from many organs within the body, but primarily originate from within the GI tract. The majority of them start in the small intestine, followed by the pancreas. Pancreatic NETs are sometimes described as a rare group of tumors, but because they tend to be slow growing, their prevalence in the United States isn’t quite as high.There are only a few thousand new cases of reported pancreatic NETs each year. It’s a relatively rare and unique type of tumor. They are often lumped in with carcinoid tumors of the small intestine, which are much more common. Although carcinoid tumors are at least 3 to 4 times more common than pancreatic NETs, they both present various challenges.

What agents are you most excited about entering the landscape?

Twenty percent to 40% of carcinoid tumors of the small intestine make hormones, the most common of which is serotonin. This causes carcinoid syndrome, which presents its own unique set of challenges in addition to the number of GI symptoms, hot flashes, etc, that patients experience. A minority of pancreatic NETs make excess hormones and can lead to very significant syndromes. Those that produce excess insulin are very difficult to manage because they cause lots of hypoglycemia. Those that produce other excess hormones can cause terrible ulcer disease.Even though NETs of the GI tract are not commonly talked about, they are fairly prevalent. Over the last 10 to 15 years, there have been at least 4 or 5 FDA approvals in this space. That has altered the treatment landscape. We have had somatostatin receptor analogs for some time, which enable us to treat the growth of the tumor as well as the syndromes. These new targeted therapies have really changed the treatment landscape.

In January 2018, Lutathera was approved by the FDA. It’s a complex treatment to deliver, so its uptake will probably be relatively slow. It will likely be centered at larger centers around the United States. Lutathera is a type of PRRT and is the primary antibody-connected radiotherapy in this space.

Yttrium-90 resin microspheres, or liver-directed therapy, is used more generically in these and other sets of tumors. It’s a radiolabeled glass bead, specifically a microscopic glass bead that is injected in the hepatic arterial system to treat liver tumors of various sorts. It’s used in NETs, colorectal tumors, and hepatoma.

Will we continue to use chemotherapy in these patients?

Will there be an immunotherapy breakthrough in the field?

Lutathera is specific for NETs, and the data derived from the European studies, including the registration study, [were] done exclusively in well-differentiated and moderately differentiated NETs. I don’t know of any other PRRT agents that are on the horizon.There was a regimen that came about from a group at NYU Langone Health on the basis of preclinical data. The data suggested that the combination of capecitabine and temozolomide had an important cell-directed cycle effect on tumor cells. A couple of small studies of several dozen patients suggested significant activity in its use. Although its efficacy has been proven, it is a difficult regimen for patients to take because they have to take 1 of the drugs 2 out of the 4 weeks and the other drug every 10 to 14 days. However, it’s well tolerated and has activity that extends to pancreatic and other GI NETs, as well.There has been a small amount of research so far on immunotherapy drugs in this group of NETs. I don’t know of any positive studies yet, so I don’t see anything on the horizon. What is important to keep in mind with regard to the evolution of NET treatment?

This is a group of tumors that a community oncologist is not likely to see much of. They might see 2 to 5 patients with these diseases. It’s nonetheless important to engage the help of specialists and emphasize the multidisciplinary nature of treatment. Nearly all of these patients will need some sort of multidisciplinary input for their treatment and care.

Strosberg JR, Wolin EM, Chasen B, et al. NETTER-1 phase III: efficacy and safety results in patients with midgut neuroendocrine tumors treated with 177Lu-DOTATATE. J Clin Oncol. 2016;34(suppl; abstr 4005). ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.4005.