Kulke Sheds Light on Emerging Agents for Neuroendocrine Tumors

Matthew Kulke, MD

Several emerging agents are rapidly advancing the treatment paradigm for patients with neuroendocrine tumors (NETs).

Lutathera (lutetium Lu 177 dotate) was approved by the FDA in January 2018 for patients with somatostatin receptor—positive gastroenteropancreatic NETs. The approval follows the findings of the phase III NETTER-1 trial, which demonstrated a 79% reduction in the risk of progression or death with Lutathera compared with octreotide LAR.¹

In December 2017, the FDA granted a priority review designation to a novel version of the radiopharmaceutical iobenguane I-131 (Azedra) for patients with malignant or recurrent pheochromocytoma or paraganglioma, which are rare forms of NETs. Under the Prescription Drug User Fee Act, the FDA is scheduled to make its decision on the NDA by April 30, 2018.

Cabozantinib (Cabometyx) is another agent showing promise in the field, based on a phase II study in patients with advanced carcinoid tumors and pancreatic NETs. The overall response rate was 15% in each of these 2 cohorts. Median progression-free survival (PFS) exceeded 20 months in patients with pancreatic NETs.²

OncLive: What exciting advancements have occurred in the treatment of patients with NETs?

In an interview with OncLive, Matthew Kulke, MD, a medical oncologist at Dana-Farber Cancer Institute, discussed the evolving treatment paradigm for patients with NETs.Kulke: There are several new treatments that are focused on tumor control for patients with NETs. For example, there is a phase II study of cabozantinib, a tyrosine kinase inhibitor that targets VEGF and c-MET. The study showed encouraging results, leading us to believe that cabozantinib will be taken forward into a large randomized trial that is designed as a registration study. Hopefully, we will get another new treatment for patients with NETs.

Other treatments include a new drug called iobenguane I-131. This is a drug that is designed for patients with a relatively rare form of NET called pheochromocytoma or paraganglioma. There are very few treatments available for these patients. Iobenguane I-131 showed encouraging activity and hopefully will move forward and represent a new treatment option for this patient population.

Regarding peptide receptor radionuclide therapy (PRRT), many are aware of the registration study that was published in the New England Journal of Medicine that showed encouraging results demonstrating that Lutathera improves progression-free survival. An example of the successful data suggests that Lutathera helps patients preserve their quality of life, which is an important aspect for those who are suffering from this disease.

A second study involving Lutathera showed that it can be given if patients had responded to the first few rounds of Lutathera and then the tumors start to grow again. In some patients, it can be given safely for a second time, so that may represent an option for patients.

A whole other area for patients who have advanced NETs include treatments that are focused on carcinoid syndrome. In 2016, the results of a study called TELESTAR were presented. A drug called telotristat etiprate (Xermelo) inhibits serotonin production in patients who have carcinoid syndrome and was approved in February 2017, making it an available treatment. We saw studies confirming and expanding our knowledge of telotristat etiprate. There were data on the long-term extension of that study, showing that telotristat can be safely given over a long period of time. The efficacy seems to continue and there were not any new safety signals in that study.

How has telotristat impacted patients’ quality of life?

A companion study called TELECAST investigated patients who did not have severe diarrhea but showed that telotristat also helped those patients. Again, we are seeing more data on some of these new treatments that are available for our patients. [Dana-Farber Cancer Institute researchers] were involved in the registration study that led to that approval, giving us some experience with this drug. It is great to have an option for patients who have carcinoid syndrome and symptoms, especially diarrhea, despite being on somatostatin analogs, since we previously did not have many options in that scenario. This represents one effective option.

If the registration trial for cabozantinib is positive, how will it be sequenced?

Can you discuss the mechanism of action for iobenguane I-131?

With the addition of PRRT to the paradigm, do you foresee any changes to the role of somatostatin?

Is there potential for immunotherapy in NETs?

We saw additional data that confirm the benefit. Data suggest that telotristat can help patients gain weight and can be safely given to patients who have carcinoid heart disease, which is one of the complications of high serotonin. One of the other aspects of this drug is that it doesn't work like your standard diarrheal. It needs to be taken regularly and the maximum effect does not kick in for several weeks. Everolimus (Afinitor) is the most commonly used first-line treatment for patients with advanced NETs. There is no clear approved second-line therapy for our patients. There are multiple treatments available, but no one has any idea how to sequence them. The way the cabozantinib trial is designed could make it the first drug that will represent a clear and effective second-line option for patients.This is a radioactive drug for the treatment of pheochromocytoma or paraganglioma. It is a strategy that has been used in the past and has been shown to be successful. This is a new form of therapy that will be more accessible for patients who have this rare type of NET.Somatostatin analogs have now formed a cornerstone of first-line treatment for patients with NETs. They have 2 advantages. The first is that they control tumor growth. Secondly, they also control hormone secretion and yet another new development is the approval of another somatostatin analog, lanreotide (Somatuline Depot), for the treatment of patients with carcinoid syndrome. There are multiple options there, as well. Somatostatin analogs continue to form the cornerstone of first-line treatment for our patients since they are well tolerated. Immunotherapy has been a huge revolution in cancer. We are seeing exciting results across many different tumor types in oncology. We have not seen that in NETs, but we are starting to get some suggestions as to why that might be. For example, NETs do not have many mutations. Another possibility is that the immune environment around NETs seems to be quiet. With the currently available first-generation immune checkpoint inhibitors, it is not clear how well they will work. Data suggest that there will be more immunotherapy targets that will become available as we better understand the immune environment of NETs.

We are interested in better understanding the immune environment of NETs to get a sense of what they are doing to escape the body's immune system. I am sure there is some type of mechanism there, but we need to discover it. If we can discover that, we can come up with new and more effective treatments.

References

1. 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).
2. Chan JA, Faris JE, Murphy JE, et al. Phase II trial of cabozantinib in patients with carcinoid and pancreatic neuroendocrine tumors. In: Proceedings from the 10th Annual NANETS Symposium; October 19-21, 2017; Philadelphia, PA. Abstract 290.