Expert Navigates Through Expanding Therapeutic Options in NETs

Scott Paulson, MD

The treatment landscape of neuroendocrine tumors (NETs) has experienced exponential growth with the addition of several new agents after decades of limited therapeutic options. Now, clinicians must focus on how to optimally sequence these therapies, said Scott Paulson, MD.

One of the most recent updates in this landscape was in January 2018 with the FDA approval of Lutathera (lutetium Lu 177 dotatate) for the treatment of patients with somatostatin receptor—positive gastroenteropancreatic NETs. Results from the phase III NETTER-1 trial, which compared Lutathera with high-dose octreotide LAR for patients with grade 1 or 2 metastatic midgut NETs, led to this approval. These findings showed a 79% reduction in the risk of progression or death with Lutathera compared with octreotide.

In addition to the long-standing role of sunitinib (Sutent), agents such as everolimus (Afinitor), capecitabine, and temozolomide have all shown significant activity in these tumors, providing multiple options for clinicians.

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

In an interview at the 2018 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Paulson, who is co-director of the Gastrointestinal Research Program for The US Oncology Network, medical director for the Neuroendocrine Research and Treatment Center at Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, discussed recent updates in the treatment of patients with NETs.Paulson: A lot has happened in the last couple of years, and there are a lot of new drugs. Classically, there has only been 1 or 2 drugs that we have been able to use for NETs, and now there is kind of an explosion of new agents, and a lot more data that has been coming out over the past 2 years.

What targeted agents are being used right now?

We are trying to focus on getting a general idea of how to sequence those agents. We are not really clear on that, and there are not a lot of data to guide us on how to use all these different things that have come into the hands of oncologists recently. A lot of the discussion is trying to piece together the best way to take patients from point A to point B.Everolimus has been approved for use in a number of different settings. Previously, it was approved in pancreatic NETs, but also garnered approvals in gastrointestinal and lung NETs. Sunitinib has been around in pancreatic NETs for some time. Capecitabine and temozolomide recently got quite a bit of data put behind them in a collaborative group effort, confirming what people have known for a while, which is that chemotherapy is fairly active in this disease. These are just more compelling tools in the tool belt.

How has the approval of Lutathera impacted the field so far?

When should clinicians consider using this versus chemotherapy?

One of the more exciting things is the use of radiopharmaceuticals with Lutathera getting approved, and now being available for use for many different patients outside of the clinical trial setting. Telotristat ethyl (Xermelo) has also received approval for management in patients with carcinoid syndrome. A lot has happened fairly recently.It is still difficult to get access to, and that is a big problem. It is not easy to administer the treatment, as it requires a lot of training. It is an expensive medication and one that insurers and patients don't really understand at this point. Providers don't really know where to sequence it either—we are not sure where it needs to go in a patient's treatment landscape. Because of that, and with it being so new, it has been a little bit challenging to figure out exactly where it fits. It is a very useful tool, the data are extremely compelling, and it is here to stay. Where and how it is going to be used for patients is still a little unclear in the United States; it is a little bit more well-established in Europe.The label for Lutathera is basically NETs below the diaphragm. It really should be considered when patients have had some degree of progression or some sort of evident tumor growth, usually radiographic. But, I would also consider it a significant clinical progression, where people's symptoms were significantly worsening while on somatostatin analogs, such as lanreotide and octreotide LAR.

With all this progress, what remains a clinical unmet that needs to be addressed in this landscape?

Are there any ongoing trials or anything in the pipeline that is particularly exciting?

What would you say is your main message that you would like the audience to take home?

This is not a treatment that should be considered right upfront, except in very special and select circumstances. It shouldn't be considered all the way at the end of the treatment algorithm either, it is probably going to be something that works right in the middle. Generally, the right spot is for somebody who is showing clear growth of their tumors on somatostatin analogs.People who have bad carcinoid syndrome, or very high functional burden of tumors, are still a very big challenge. It is still difficult to shrink these cancers outside of surgery and embolic techniques. Medically, it is a big step forward to have Lutathera, where the response rate was up in the 20% range in additional studies outside of Europe. There are actual studies that show Lutathera can shrink and reduce tumors, whereas other agents like everolimus, lanreotide, and octreotide LAR, have very low response rates. We need agents that can reduce symptom burden and size of tumor. That is going to be one of the things that we are going to see a little bit more movement with as the field moves forward.Immunotherapy is interesting. We don't know exactly how well it is going to work, who it is going to work for, or what settings to use it in, but those studies are currently ongoing. We are going to see some additional radiopharmaceutical agents in the vein of Lutathera and alpha emitters. There are additional ways that you can target the same targets as Lutathera to try to maximize your effect and get additional tumor shrinkage. All of those are going to continue to funnel through the pipeline, and we are going to see some fairly compelling results out of them.This is a rare tumor, but a lot of people are living with it, and a lot of things have happened. There is a lot more beyond somatostatin analogs, which are still the staple of treatment. However, there are an awful lot of options to try to reduce tumor burden from a medical oncology perspective. This has classically been a surgical disease, as well as a radiology and interventional-based disease, and we are seeing a lot different changes. It is still too soon to tell the best way to sequence all of these agents, and a lot of that requires a fair amount of feel, as well as patient-dependent factors to justify the decision. It’s changing a lot, and we are going to see a lot more approvals come through and a lot more tools in the tool belt to use.

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).