Developments With Gastrointestinal NETs Continue to Grow

Diane Reidy-Lagunes, MD

2017 was an important year for patients with neuroendocrine tumors (NETs). Diane Reidy-Lagunes, MD, said the phase III NETTER-1 trial comparing Lutathera (lutetium [177Lu] oxodotreotide) plus best supportive care versus octreotide (Sandostatin) LAR was a significant development in the treatment of patients with advanced midgut NETs.

“There was an improvement in terms of progression-free survival (PFS) with 33 months for the Lutathera arm versus 8.3 months for the [control] arm,” explained Reidy-Lagunes.

Quality of life was also much higher in the Lutathera arm than in the high-dose octreotide arm. The median global health status improved 28% with Lutathera versus 15% with octreotide and worsened in 18% versus 26%, respectively.

OncLive: Please provide an overview of your presentation on GI and pancreatic NETs.

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Gastrointestinal Cancers, Reidy-Lagunes, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed ongoing developments for the treatment of patients with gastrointestinal (GI) and pancreatic NETs.Reidy-Lagunes: I gave an overview on the treatment of NETs, which is changing quickly, but also how you diagnose and define the patient and develop personalized medicine.

Currently, what challenges do we have with diagnosing NETs?

One of the struggles with our disease is that it is quite heterogeneous. How you define and care for a patient depends on multiple factors. I gave an overview on how one can define appropriate treatment. Unlike other malignancies, this is a cancer that does not have sequencing trials of what therapy should be given first, second, or third. It depends on the different patients that you are treating. The good news is that we are finding these tumors but we hope we can find them earlier, which will translate into overall improvement and hopefully more cures. We have not yet figured that out though. Eventually, our data will tell us that, but we know that incidence is increasing at an exponential rate. We believe that is because we are picking them up. The hope and expectations are discovering it earlier, which will translate to better outcomes.

Many patients are still developing metastatic disease. We do not have any markers or ways to screen for these tumors, unfortunately. When a patient goes for general screening for a colonoscopy, a big take-home message is to try to push through into the terminal ileum because that is one of the most common places that NETs can hide. By doing that, we are picking out more terminal ileum masses that turn out to be carcinoid or NETs. That unquestionably will increase the chances of cure.

Looking back on 2017, what are some of the exciting advancements that you have seen with NETs?

From that perspective, endoscopies and rectal NETs are being picked up earlier, which is great. Upper endoscopies that are being done for other reasons are incidentally finding these tumors. There are many opportunities through endoscopy but we still have not defined lung NETs or pancreatic NETs because there is no real screening for those. It has been a great year for NETs since there have been a couple of treatments that have increased either by quality or quantity. Peptide receptor radionuclide therapy was a home run in this field. The NETTER-1 trial took patients that had already received octreotide, which is our first-line therapy, and randomized patients to higher-dose octreotide and Lutathera peptide receptor radionuclide therapy.

We do not usually get numbers like that in oncology. The hope and expectation is that patients with somatostatin avid disease will benefit from this. That study was only in midgut disease, so it is at the FDA now for consideration of treatment with Lutathera for any patients with somatostatin avid disease, whether it is small bowel or in all-comers who have NETs. It is a major milestone.

There are rare and serious adverse events that we need to consider. There is a rare risk of myelodysplastic syndromes and leukemia but patients generally can get tremendous benefit.

What other trials are ongoing that you are excited about seeing the results of?

Then we have telotristat (Xermelo), which is a drug that is used for the carcinoid syndrome. It is a nice medication to have for patients who have carcinoid syndrome with refractory symptoms, such as diarrhea or flushing. Having this overall therapy to help them improve their bowel movements and their flushing is another additional treatment to provide. It is a great year, but we still have more to come and we need to continue to do the work.There are a couple of trials that we are waiting on. There is a trial in pancreatic NETs that uses chemotherapy, particularly the combination of temozolomide plus capecitabine. In a small phase II trial, the combination had a high response rate of 70%, but it was only one phase II trial that was not randomized. This study asks the question of, “Is temozolomide enough or do you have to combine it with capecitabine?” It will be an important trial.

There is an unmet need with poorly differential NETs. In collaboration with a doctor at University of California, San Francisco, we have a trial of pembrolizumab (Keytruda) in poorly differentiated NETs, which we are all excited to see the results of. There are also immunotherapy trials in NETs as well that we are hopeful to see. Those are opportunities that we are eagerly waiting on.

In the study of pembrolizumab in poorly differentiated NETs, did the patients have microsatellite instability-high (MSI-H) tumors?

In the next few years, what does the ideal treatment paradigm look like for patients with NETs?

Dr Jennifer Chan has a cabozantinib (Cabometyx) study that was positive. That is a phase III study that we are excited about in pancreatic NETs. There are many things that are coming down the pipeline. We may have patients that are MSI-H, but we are not enriching for the patient population. We have not found a high number of MSI-H tumors in those patients with poorly differentiated NETs. We are trying to extrapolate from small cell lung cancer (SCLC), where there are also not many MSI-H tumors, and yet they have high activity. The hope is that potentially given the similarities of our disease to SCLC, we would see some activity. We always want the cure. If we could do that in a couple of years that would be great but that is probably unlikely. We would love to define and personalize approaches for each patient. Unfortunately, we do not have the data to help us sequence treatments to determine which should go first, second, third, or fourth, but we have new technology.

If we could use that technology through genetic sequencing and biomarkers, we could define patients genetically to better understand their disease, their prognosis, and tailor the therapies for that patient. If we can define who would do better with a treatment later versus earlier that would be important. We already have signs that patients with smaller burden of disease would do better, but there is selection bias since they have better biology.

Is there anything else you would like to add?

Overall, trying to use the technology that we have in order to personalize the therapy better would be ideal. It is an exciting time for NETs since there are many different therapies to offer. For every therapy, we are constantly thinking about the quality and quantity of the patients’ lives because we want to ensure that our patients can live long and well. We also want to ensure that we do not put them in harm’s way. We have to be careful about using the therapies at the right time.

Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-135. doi: 10.1056/NEJMoa1607427.