Influx of Therapies in NETs Prompts Questions Over Combinations and Sequencing

Diane Reidy-Lagunes, MD

Tyrosine kinase inhibitors (TKIs), hypoxia-inducible factor 2α (HIF-2α) inhibitors, and peptide receptor radiotherapy are generating excitement in the field of neuroendocrine tumors (NETs), explained Diane Reidy-Lagunes, MD. However, until more definitive data are available regarding the optimal sequence of treatment, recommendations should be based predominantly on the patient, the location of their disease, and their performance status.

“In the past year, the promise of additional therapies and potentially altering therapies in order to maintain quality of life [has been] worked [on] on the investigative side,” Reidy-Lagunes said. “In the past year, there has not been an FDA-approved drug in the United States [specifically for NETs], although over the past 5 years, the landscape has really changed. Therefore there are multiple therapies to consider.”

In an interview with OncLive^®, Reidy-Lagunes, associate deputy physician in chief of Regional Care Network, physician ambassador for the Patient Family Advisory Council for Quality, and president of Memorial Sloan Kettering Cancer Center Medical Staff in New York, New York, unpacked recent updates in NETs. She also provided insight into the presentation she will deliver on NETs during the 39th Annual Chemotherapy Foundation Symposium^®.

OncLive: How has the role of TKIs evolved in NETs?

Reidy-Lagunes: Many therapies are available for [patients with] NETs, including somatostatin analogues, targeted therapies, peptide receptor radiotherapy, and chemotherapy. However, [it’s important to discuss] findings from 2021 that perhaps haven’t reached community oncologists yet.

The role of lenvatinib [Lenvima] in gastrointestinal [GI] NETs is important. Findings from the phase 2 TALENT study [NCT02678780] showed a response rate of 44% in pancreatic NETs and 16% in GI NETs, which is the highest reported response rate in GI cancers.

Another important drug is surufatinib, which was evaluated in 2 studies in China [NCT02589821; NCT02588170] and approved in China for patients with pancreatic NETs and extra-pancreatic NETs. The response rates ranged from 10% to 20%. In July 2021, the FDA accepted the filing of a new drug application for surufatinib for patients with pancreatic and extrapancreatic NETs, so we should hear whether that agent is approved for use in the United States soon.

The role of TKIs in NETs is evolving and moving forward, which is exciting. There have been multiple reports that indicated the role of sunitinib [Sutent] could be promising, [including from] a randomized phase 2 study [FIRSTMAPPP; NCT01371201] of sunitinib in pheochromocytoma/paraganglioma. The study met its primary end point; the 12-month progression-free survival [PFS] rate was 36% with sunitinib vs 19% with placebo. The role of different types of TKIs will be further discussed [at the meeting] and are promising [agents] to look out for.

Which studies have underscored the importance of personalized treatment in NETs?

There was an important study on mortality in NETs that was published in the Journal of the National Comprehensive Cancer Network. Investigators looked at a retrospective registry of 8607 patients from Toronto. In patients with small intestine, colon, and rectal NETs, the risk of non–cancer-associated death outweighed the risk of cancer-specific death. In our patient population, one of the biggest challenges is the heterogeneity of the disease. Some patients can live with the disease and some patients pass because of the disease. Being mindful that not every patient needs aggressive treatment is critical. In the study, it was noted that [patients with] bronchopulmonary NETs and pancreatic NETs usually succumb to the dis-ease because these tumors tend to have a more aggressive pattern. This study [emphasizes the importance of] knowing your patient. It is possible to wait on [treating] certain patient populations, so that we don’t over treat. Many patients with GI NETs can pass from other non–cancer-related problems, and it is important to be mindful of that.

What was exciting about the approval of the HIF-2α inhibitor belzutifan (Welireg)?

In August 2021, the FDA approved belzutifan. The drug was approved for patients with germline mutations for von Hippel-Lindau syndrome, which is common in pancreatic NETs. The pivotal phase 1 Study 004 [NCT03401788] enrolled 61 patients with the von Hippel-Lindau germline gene mutation, and the primary end point was objective response rate [ORR]. The ORR was [at least] 49% [across all subgroups, and] the duration of response was at least 12 months [in most patients].

How are you utilizing the peptide receptor radiotherapy lutetium 177 (177Lu)-Dotatate (Lutathera) in this space?

177Lu-Dotatate is a game changer for patients. It consists of 4 treatments every 8 weeks and then patients are done, which is nice. My mentor used to tell me grade 1 to 2 nausea every day is probably worse from a patient quality of life perspective than grade 3 nausea for 2 days. It is important to be mindful of the adverse effects [AEs] of the different therapies given to patients. Peptide receptor radiotherapy is a nice therapy because the chances of long-term AEs are rare, but serious.

Patients can have lower blood counts and there’s a rare but serious risk of preleukemia and leukemia [with peptide receptor radiotherapy]. In general, those are therapies that are well tolerated. They’re not readily available to every-one. In the community, often you must submit a referral to an academic center to be able to provide that treatment, but more and more providers are able to find an appropriate place to be able to give patients the therapy that is needed.

The role of peptide receptor radiotherapy, which has altered the way that patients are cared for now that it is FDA approved in the United States, is evolving as well. It is important to ask the question should we add therapies onto that treatment or should we sequence treatments. The right sequencing of therapies is unknown. Many studies are ongoing now to test the role of combinations with that treatment. At this point, we do not recommend any combination of treatments with 177Lu-Dotatate.

Without level 1 evidence, how do you approach treatment sequencing?

The biggest challenge, which I’ll address during my talk, is that we don’t know what the optimal sequencing strategy is. What is the best second- and third-line treatment? Often it depends on the patient as well as the location of their disease and their overall performance status. In a patient with high tumor burden where the goal is tumor shrinkage, you may try a combination of oral cytotoxic therapies, whereas in a patient that has low-volume disease and is asymptomatic, you may be able to just watch for a while. That personalized approach in NETs can be challenging because we don’t have great data to help us drive the different lines of therapies that we have. We don’t have enough of a patient population to be able to do sequencing studies in an accurate and efficient way.

Could immunotherapy become part of the NET paradigm?

The role of immunotherapy in NETs still is a work in progress. Several trials with well-differentiated NETs failed to meet their primary end point of response. One trial in poorly differentiated carcinomas did show some promise, but unfortunately other studies failed to show that [same promise].

Other studies are trying to manipulate the immune system, but it doesn’t look like NETs are hot tumors, potentially because these are tumors without alterations and without high mutational burden. There are many reasons why the immune system doesn’t recognize the NET as well as it does other tumors. There are some virus-type protocols with immunotherapy that are coming, so there’s more to come. However, in well-differentiated NETs, there is currently no role to use checkpoint blockade.

Are you or your institution involved in any trials that you would like to highlight?

A study is evaluating cabozantinib [Cabometyx], which is another TKI we’re excited about. Patients will be randomized to cabozantinib or placebo, and because it allows for crossover, accrual is picking up. For anyone who’s involved in cooperative group studies, I would consider that trial because it is import-ant for our patient population to potentially have that extra therapy.

Additionally, the RETNET study [NCT02724540] is looking at different types of embolization. There’s radioembolization, bland embolization, and chemoembolization, and no prospective study has been done to examine which type of embolization is safer and/or better.

With chemoembolization, there was a drug-eluting bead arm in the trial, which was dropped because of toxicity. For those who do embolization, don’t use drug-eluting beads because it was shown to be quite toxic. Now we’re comparing lipiodol chemotherapy embolization vs bland embolization.

Finally, there is a study [LUTIA; NCT03590119] of intra-arterial peptide receptor radiotherapy testing the potential role of giving liver-directed 177Lu-Dotatate, as opposed to systemic 177Lu-Dotatate, to see whether that could decrease toxicity and increase efficacy in patients with liver-predominant disease. Overall, we’re focusing on quality and quantity. All the studies tried to ask what’s the best therapy for our patients in terms of QOL, which is important.

As the moderator of the symposiumʼs GI track, could you preview some of the topics that will be highlighted?

There are many terrific speakers in the GI malignancies track. We tried to [organize the agenda] from the upper to the lower GI tract, including gastroesophageal, hepatocellular carcinoma, pancreas, [and] colorectal cancers. I’m proud of the speakers [we have] and I know that interesting topics will be covered.