Excitement Continues to Build for Advances in Neuroendocrine Tumor Field

James C. Yao, MD

It’s been an exciting year thus far for patients with neuroendocrine tumors (NETs), with the FDA approving a new treatment regimen and more advancements on the horizon, according to James C. Yao, MD, a professor in the Department of Gastrointestinal (GI) Medical Oncology at The University of Texas MD Anderson Cancer Center.

In February, the FDA approved everolimus (Afinitor) as a treatment for patients with progressive, well-differentiated, non-functional NETs of GI or lung origin with unresectable, locally advanced or metastatic disease. The mTOR inhibitor has been approved since 2011 for unresectable or advanced pancreatic NETs.

Meanwhile, the agency is evaluating Lutathera (177Lutetium DOTA-octreotate), a peptide receptor radionuclide therapy (PRRT), for patients with gastroenteropancreatic NETs under its priority review program. Similarly, telotristat etiprate, a small-molecule tryptophan hydroxylase inhibitor, also is being considered under the FDA’s priority review program for carcinoid syndrome in patients with metastatic NETs.

OncLive: Please summarize the highlights of neuroendocrine advancements.

Yao sat down with OncLive at the 2016 World Congress on Gastrointestinal Cancers in July to discuss developments in the field.Yao: The last year has been a big year for neuroendocrine tumors. There were 3 positive phase III studies. One included everolimus in lung and GI neuroendocrine tumors; that study has already been published in Lancet in March.¹ It received the FDA approval late in February.

Another study that was reported was the NETTER- 1 study.² This is a prospective randomized phase III study of Lutathera (177-Lu-Dotatate) versus octreotide. The study showed significant benefit in terms of progression-free survival. The publication and the health authority decisions are still pending at this time.

Finally, there was a phase III study of telotristat.³ This is an agent targeting a fairly rare condition, refractory carcinoid syndrome. The study did meet its primary endpoint. It was a fairly short 12-week study that compared, essentially, either placebo plus standard treatment of a somatostatin analog or 2 doses of telotristat at 250 mg and 500 mg.

What can you tell us about next-generation somatostatin analogs, particularly pasireotide?

The study showed a significant decrease in bowel movement count. It is less than, on average, 1 BM per day from their baseline. But nonetheless, it was a positive study. Publication and health authority decisions are still pending.The current generation of somatostatin analogs mostly target somatostatin receptor-2 and, to some extent, somatostatin receptor-5, and these are octreotide and lanreotide. There are new agents on the horizon that target a broader profile of somatostatin receptors. These include pasireotide, which targets somatostatin receptors 1,2,3, and 5. Its utility in refractory carcinoid syndrome was also explored in a phase III study, but because of the study design and the limited number of patients, I don’t think this study really fully answered the question.

Where does telotristat etiprate fit in?

Nonetheless, in that study there were some hints that it may have some efficacy in terms of further delaying disease progression compared with regular somatostatin analogs. Whether those will be explored in future trials remains an unanswered question at this time.Telotristat is a little bit different. It doesn’t target the somatostatin receptor, but specifically serotonin. So I really think this is going to be limited to control refractory diarrhea.

What is the potential for PRRTs in development for NETs?

There are 2 components for carcinoid syndrome, and that’s flushing and diarrhea, with serotonin being the one that’s responsible for the diarrhea component. So that’s where telotrisat will likely have its role—in patients with refractory diarrhea from neuroendocrine tumors.Peptide receptor radiotherapy is using this somatostatin receptor in a different way. You can use the ligand in the peptide, in this case to deliver a radioisotope to the tumor.

Because some of the isotopes that are being used include indium, yttrium, and lutetium, the agent probably best studied is the lutetium label compound. That’s what the NETTER-1 study was about. Previously, there have been a lot of single-arm case series or potentially single-arm studies showing activity. NETTER-1 showed a randomized control study for midgut neuroendocrine tumors and the utility of PRRT in this group of tumors in delaying tumor growth.

There are some other compounds out there, including yttrium-labelled dotatoc, and also I think a compound that looks at a somatostatin receptor antagonist that may better deliver isotopes. So clinical trials with these other agents are also ongoing.

One limitation for peptide-receptor radiotherapy is that, even though it works, you cannot keep repeating the treatment because you will get trouble in terms of bone marrow toxicity, secondary malignancies, and renal issues.

How do you think treatment of neuroendocrine tumors will be different in 5 or 10 years?

There are also other ways of targeting somatostatin receptor that are being explored. For example, there is a study that will look at an agonist peptide targeting somatostatin receptor-2, but instead of being tied to a radioisotope, it is tied to a DM1, which is a peptide—drug conjugate. [The goal is] to use the peptide to deliver a toxin rather than deliver a radioisotope. There are many of these options out there.That’s a loaded question in some ways. Given the time horizon for drug development, what can be affected in terms of standard-of-care treatment 5 years from now are mostly the ongoing phase II studies that we’re talking about. For example, there’s also a randomized phase II trial of pazopanib versus placebo that has just finished accrual, so we’re waiting for those studies. Further investigation of VEGF inhibitors in neuroendocrine tumors outside the pancreas is already approved. Sunitinib is approved for pancreatic tumors. Whether VEGF inhibitors have a role outside the pancreas hopefully be answered in that sort of time frame.

References

1. Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebocontrolled, phase 3 study. Lancet. 2016;387(10022):968-977.
2. Strosberg J, Wolin E, Chasen B, et al. NETTER-1 phase III: efficacy and safety results in patients with midgut neuroendocrine tumors treated with 177Lu-dotatate. Ann Oncol. 2016;27(suppl 2):ii118- ii128. Abstract O-009.
3. Kulke MH, Hörsch D, Caplin M, et al. Telotristat etiprate is effective in treating patients with carcinoid syndrome that is inadequately controlled by somatostatin analog therapy (the phase 3 TELESTAR clinical trial). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 37LBA.