NETs Treatment Arsenal Expands, With More Progress on the Horizon

Lowell B. Anthony, MD, FACP

The addition of everolimus (Afinitor) and telotristat ethyl (Xermelo), to the treatment arsenals in neuroendocrine tumors (NETs) and carcinoid syndrome, respectively, is helping to achieve disease control and manage adverse events (AEs), said Lowell B. Anthony, MD, FACP, and several emerging therapies have the potential to push the envelope even further.

“This is a new day in the management of NETs,” said Anthony, chief of the Division of Medical Oncology at the University of Kentucky Markey Cancer Center. “We have myriad treatments, procedures, and agents available, which are allowing us to improve patient symptoms and outcomes, specifically in terms of survival and quality of life.”

In addition to the somatostatin analogues, targeted therapies, and chemotherapies that make up the current standards of care, VEGF TKIs, monoclonal antibodies, and immunotherapies are also gaining traction in the space. Beyond the available therapeutic strategies on the market, one of the biggest challenges moving forward will be understanding how to best sequence these options, said Anthony. However, patient factors, such as tumor bulk and disease grade, can be used to inform these decisions, he added.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Neuroendocrine Tumors, Anthony shed light on important data that have shaped the current NETs treatment paradigm and highlighted notable ongoing studies.

OncLive: What key practice-changing trials in NETs do you wish to highlight?

Anthony: What was amazing about the RADIANT-2 trial is that it was the very first trial to give us an indication that there was an active agent, for lung NETs: everolimus. We never had anything in this space before. The somatostatin analogue octreotide was FDA approved for carcinoid syndrome, but not lung NETs. It did take the RADIANT-4 trial for [everolimus] to get registered as an agent in NETs, not only [in tumors] of the lung but also the gastrointestinal (GI) tract. The pancreas primary tumors had been registered about 5 years earlier in 2011.

Could you expand on the data yielded from the RADIANT trials?

RADIANT-2 did not achieve statistical significance; it missed it by .001. There were some irregularities [in that trial] as it relates to the randomization process, but what was interesting is that there were different primary tumor types collected. We know the biology is different. RADIANT-2 did not have an equal distribution of primary sites in the final study, so this was an event that occurred at random. As a result, Novartis, the sponsor of the trial, was basically forced to conduct RADIANT-4.

The difference between these studies was that they went from having to combine with a somatostatin analogue to now working with nonsyndromic patients. Now, they could take patients with lung primaries and other primaries and not require the somatostatin analogs, because that was considered the standard of care. They were able to get a more homogeneous group of patients, not require the somatostatin analogues, and were able to show statistical significance. That was really practice changing. RADIANT-2 did not by itself stand alone, but it certainly gave us clues as to where everolimus was going to be useful.

What is the role of serotonin in carcinoid syndrome?

We know that serotonin is a key mediator in carcinoid. We know that there are basically 3 areas of the body where serotonin is made. One is in the enterochromaffin cells that line the gut epithelium, another is the plexus of the GI tract, and the third is the central nervous system. A few years ago, we had an inhibitor of serotonin synthesis introduced into the standard of care.

This was about 5 years after the TELESTAR trial was initiated and eventually had the drug approved for diarrhea that's not adequately controlled with a somatostatin analogue. Telotristat ethyl inhibits the first enzymatic process in the conversion of dietary tryptophan to serotonin, is used in conjunction with the somatostatin analogues, octreotide (Sandostatin) or lanreotide (Somatuline Depot), in the management of carcinoid syndrome.

What were key data from the phase III TELECAST trial?

The TELECAST trial is a randomized, prospective, multicenter trial that spanned 90 days. It took patients with carcinoid syndrome who had inadequate control of diarrhea. They were able to decrease the number of stools per day by almost 1.5 incidences per day [with telotristat ethyl]. It doesn't sound like a lot, but if you're in the 4-times-a-day-range and you decrease it to under 3, that's a huge decline from a patient's perspective.

What we were also excited about was the secondary endpoint with [the agent]. We saw a dose-related decrease of 5 hydroxyindoleacetic acid or serotonin. Telotristat not only controls the symptoms, but it also lowers the body's exposure to serotonin that's being overproduced by these malignant cells that are mostly in the liver. They could also be in the lymph nodes and in the bone, in some cases.

What is the role of chemotherapy here?

The role of chemotherapy in sequencing therapy mostly focuses on the well-differentiated grade 2 or the pancreatic primaries where we have chemotherapy choices like capecitabine in combination with temozolomide. The real advantage here is that we have a high response rate [with this approach]. The trial that was reported last year at the 2018 ASCO Annual Meeting showed a 33% response rate. We can adequately decrease the amount of disease with this combination, so that the patients who have high tumor bulk can not only have controlled disease, but reduced disease. We see disease control for a median of 18 months, and for some patients it might be years.

What advice would you give in terms of sequencing?

The sequencing of chemotherapy and targeted therapy is such that we now have choice. Generally, the backbone of management [in this space] are the somatostatin analogues. When patients fail the somatostatin analogues, this is where sequencing comes in. If they have high bulk and grade 2 disease, then patients would probably benefit from capecitabine and temozolomide, maybe even before the somatostatin analogue. If they are syndromic, chemotherapy will [typically] be given in combination with somatostatin analogues. If a patient fails the somatostatin analogues or does not have high tumor bulk, then the use of everolimus or sunitinib (Sutent) becomes a choice. [At that point], it's really dealer's choice; there are no data-driven information guiding us. Basically, the patients are going to receive an mTOR inhibitor, everolimus, and a TKI, sunitinib.

We now also have peptide receptor radionuclide therapy (PRRT), which is another alternative option in the sequencing of these therapies. Do we do PRRT after patients fail the somatostatin analogues? In some patients, do we start with PRRT? What do we do in patients with widespread, bony disease? The really good news is that patient outcomes are significantly better now than they have ever been in terms of disease control. We also have more choices [to choose from]. We can control the known AEs of the disease and not have unexpected toxicities.

What are some emerging therapies to look out for?

Emerging therapies that we should be aware of would include the TKIs for grade 1, well-differentiated intestinal NETs. Trials with cabozantinib (Cabometyx) and lenvatinib (Lenvima) show promise. The cabozantinib trial is in progress, so it's just a matter of 2 to 5 years before we have more options in GI NETs, similar to what we have in pancreatic NETs. Other areas [of research] will be immunotherapy. The trial that was reported recently in Europe looking at spartalizumab (PDR001) showed benefit for [those with] thoracic NETs. In other areas, immunotherapy is going to be a little bit more challenging, but it’s definitely an emerging area.

Spartalizumab is a PD-L1/2 inhibitor; it is a monoclonal antibody. [The agent] has been tested in prospective randomized trials in not only 3 primary sites, but also in nondifferentiated NETs. From the trial that was done, we can see that there were more responses in these thoracic primaries. Historically, there was another trial with pembrolizumab (Keytruda) suggesting response rates around 6% to 12%. We're not quite pleased with these early signals, although we are not sure how it'll translate to practice. It's probably too early to tell.

There was also the TALENT trial with lenvatinib, which showed us some of the highest response rates that we've seen in NETs. This is being in the resistant phase. It was remarkable to see such activity.

SWOG-0518 is a trial where the combination of octreotide and bevacizumab (Avastin) was compared with octreotide and subcutaneous interferon. This was a large trial that took about 10 years to conduct with over 400 patients. Although the response rates were higher in the bevacizumab arm, the progression-free survival benefit was very similar. This trial told us that getting a highly specific monoclonal antibody to VEGF is probably not going to be a strategy that will be used going forward.

What is important for your colleagues to take away from this insight?

We now [agents to choose from] in the management of patients with NETs. If the syndrome symptoms are not adequately controlled with the somatostatin analogues, lanreotide or octreotide, we now can use several different agents to control the symptoms without putting the patients at risk for additional toxicities.

There has never been a better time in managing these patients. Patients are very much individualized, and our ability to choose what we think is the best personalized therapy for that patient is such that now we expect these patients to live for many years. That is starting to show in recent data.