Deeper Understanding of NETs Biology May Hold Key to Therapeutic Advances

Lakshmi N. Rajdev, MD

As a greater understanding of the biological differences across neuroendocrine tumor (NET) subtypes is observed, other therapeutic strategies beyond somatostatin analogs are coming to the forefront, said Lakshmi N. Rajdev, MD.

"Somatostatin analogs have been the cornerstone of treatment for patients with NETs," said Rajdev. "They have very modest activity in terms of response rates, but they play an important role in the treatment of [patients with] carcinoid syndrome and can ameliorate a lot of symptoms, like diarrhea."

One novel approach has been peptide receptor radionuclide therapy (PRRT). In the phase III NETTER-1 trial, Lutathera (lutetium Lu-177 dotatate) was compared with high-dose octreotide LAR (Sandostatin) for patients with metastatic or locally advanced, inoperable, well-differentiated midgut NETs who progressed during treatment with standard-dose octreotide LAR. Earlier findings demonstrated a 79% reduction in the risk of progression or death with Lutathera, and led to the FDA approving Lutathera in January 2018 for patients with somatostatin receptor—positive GEP-NETs.¹

Moreover, updated progression-free survival results showed 30 events in the Lutathera arm compared with 78 events in the octreotide LAR arm. Lutathera was also better tolerated in terms of global health status, fatigue, and physical functioning.²

These data led to the January 2018 FDA approval of Lutathera for patients with somatostatin receptor—positive gastroenteropancreatic (GEP)-NETs.

"Understanding the differences [in tumor types] is key,” said Rajdev. “In practice where physicians are seeing more common tumors like breast, lung, and colon, NETs are somewhat rare, so it's important to understand the differences in biology between these tumors and the various approaches for them.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Rajdev, an associate professor, Department of Medicine (Oncology), at Albert Einstein College of Medicine, Montefiore Medical Center, discussed classifying and grading NETs, treating patients with NETs, and novel therapeutic strategies in the pipeline.

OncLive: What are the main studies that have read out in this space?

Rajdev: Randomized studies, such as CLARINET, have led to the approval of somatostatin analogs. These studies differ for octreotide as well as lanreotide (Somatuline Depot) and with PRRT, because these have been conducted in different patient populations at various time points of the disease.

For instance, in the [PROMID] study, it's unknown whether patients were progressing or they had stable disease, while the CLARINET study was done in patients with stable disease. The NETTER-1 trial was done in patients who have progressive disease.

Also, different patient populations have been included in different studies. Some have included GEP-NETs, and some have solely included pancreatic NETs; highlighting some of these differences is important as well.

Additionally, there are phase III studies that have been done in pancreatic NETs for everolimus (Afinitor) and sunitinib (Sutent).

How could immunotherapy be used in this space?

Unfortunately, immunotherapy has not shown the promise that it has in other diseases. There was a study done with pembrolizumab (Keytruda) in about 110 patients, but the response rate was only 3.7%.

Other checkpoint inhibitors have also been investigated with similar results. Though at the 2019 AACR Annual Meeting, there was a presentation with nivolumab (Opdivo) and ipilimumab (Yervoy) and promising responses were observed. Those data are very preliminary, so we have to stay tuned as to whether dual inhibition is the way to go in patients with neuroendocrine carcinomas.

Has any other research demonstrated promising activity?

There was a study presented at the 2019 ASCO Annual Meeting with pazopanib (Votrient). Unfortunately, it showed very modest activity. We're not seeing clear, emerging winners in the field yet, but there are several agents that are being investigated.

Cabozantinib (Cabometyx) is also being investigated. We are looking at multiple TKIs as well. We will just have to wait and see what happens in the cabozantinib study as the pazopanib study, unfortunately, had just modest activity.

What is the different between carcinoids and carcinomas in neuroendocrine tumors?

That is very important. There are differences and some of the terminology is confusing for the average person in practice.

For instance, patients with neuroendocrine cancers have a different course [of treatment] than those with neuroendocrine carcinomas. Neuroendocrine carcinomas, particularly the high-grade ones, are clinically aggressive and could have large- or small-cell components. It is defined as a carcinoma if there's ≥30% of a neuroendocrine component, as well as a carcinoma component.

These tumors are so aggressive that they need to be treated with etoposide and either carboplatin or cisplatin. On the other hand, grade III neuroendocrine cancers are defined as patients who have a Myotonic Dystrophy Health Index >24 high-power fields or a Ki-67 of >20%. These patients have an outcome that is somewhat in between the more indolent NETs and these high-grade carcinomas.

Typically, these patients are treated with traditional agents, such as everolimus. If there is extensive bulky disease and patients are symptomatic, capecitabine (Xeloda) and temozolomide (Temodar) are reasonable approaches. Otherwise, they could be treated in the way you would treat low-grade NETs.

Could you expand on the use of somatostatin analogs?

They have also been shown to improve PFS, which led to their approval in the management of low-grade NETs. The real question is, “When is the optimal time to introduce these agents?” That is where the great debate lies.

For instance, if someone has indolent disease, they could remain stable for extended periods of time. There is no need to treat these types of patients with somatostatin analogs. If they had developed progressive or symptomatic disease, then it's reasonable to potentially treat them with somatostatin analogs. Additionally, if someone has more extensive disease, it's reasonable to start somatostatin analogs upfront.

The other question that physicians grapple with is, “Do we continue somatostatin analogs when patients have disease progression or not? How does one manage that?”

In general, a reasonable approach is to discontinue the drug if patients clearly developed progressive disease on a somatostatin analog. Conversely, if patients have hormone secretion or have carcinoid syndrome, it's reasonable [to continue] since these analogs have demonstrated activity in carcinoid syndrome and hormonal syndrome management.

Additionally, there is no benefit of switching somatostatin analogs. If a patient is on octreotide and they have disease progression, switching to lanreotide may not necessarily benefit them.

What other strategies are important to note in these patient populations?

Carcinoid syndrome is seen more commonly in patients who have liver metastases and midgut tumors. It's less frequent in patients with lung carcinoids.

Liver-directed therapies are important in the management of these patients. Therefore, if patients have liver metastases that are able to be resected, then that would be a tremendous approach.

On the other hand, there are numerous other approaches such as chemoembolization, radioembolization, bland embolization, transarterial chemoembolization, and radiofrequency ablation. It has not been shown that one therapy or intervention is superior to the other. Understanding the type of disease will help optimize the approach to the management of liver metastases.

What is the key takeaway for physicians treating patients with NETs?

Understanding the biology of the disease is important, and that's why grading is important. Also, understanding when to initiate therapy is key. If someone has high-volume disease and is symptomatic, they may benefit from early intervention.

Understanding management strategies for NETs, both pancreatic and carcinoid, and neuroendocrine carcinomas is important.

References

1. Strosberg, J, El-Haddad G, Wolin E, et al. Phase III trial of 177Lu-Dotatate for midgut NETs. N Engl J Med. 2017;376(2):125-135. doi: 10.1056/NEJMoa1607427.
2. Strosberg JR, Wolin EM, Chasen BA, et al. First update on overall survival, progression-free survival, and health-related time-to-deterioration quality of life from the NETTER-1 study: 177Lu-Dotatate vs. high dose octreotide in progressive midgut neuroendocrine tumors. J Clin Oncol. 2018;36(suppl 15; abstr 4099). doi: 10.1200/JCO.2018.36.15_suppl.4099.