PRRT continues to be used very extensively by the NET community. Ultimately, in terms of the number of patients treated per year, its use in other tumor types may predominate, but PRRT is probably one of the most integral modalities of treatment in the neuroendocrine space right now. It is quite well tolerated and can be very effective at controlling advanced gastroenteropancreatic NETs—both the disease and its symptoms. Lutetium Lu 177 dotatate was approved by the US Food and Drug Administration (FDA) in 2018, and it is given in addition to the SSA therapy. Patients receive PRRT every 8 weeks or so for a total of 4 doses, spanning approximately 6 to 8 months. So, while it is not a treatment that can be completed quickly, it is effective and well tolerated.

As relates to symptom control, and specifically diarrhea in carcinoid syndrome, telotristat is a relatively recent addition. It was approved by the FDA several years ago, and, when used in combination with SSA therapy, it decreases serotonin production and helps to manage syndromic diarrhea.

But I would say that PRRT has dominated the NET research landscape in recent years, and new PRRT studies are also planned for the years ahead. As we look to the horizon, I think that it is important to remember that there are other modalities that may be useful for these patients, and we need to keep focusing on those as well. Some of the ideas on the horizon include determining if immunotherapy or the addition of agents targeting DNA repair mechanisms might, in some way, be used, perhaps in concert with radiation therapy. There has been some recent work examining PRRT retreatment, but I think that the clinical trials that are probably going to garner the most interest from patients and physicians going forward are the PRRT trials that incorporate alpha particles.

On the immuno-oncology front, Xianxin Hua, MD, PhD, here at the University of Pennsylvania, has been working to identify tumor-associating antigens in NETs that may be targetable. Previously, several groups have tried to target serotonin receptors immunologically, but this has not been successful. CDH17 is a novel target that Dr Hua is working with, and it is being developed into a CAR T-cell construct. The idea is to try to target something that is not currently being targeted by our other agents. CAR T-cell therapy has historically not been highly beneficial in patients with solid tumors; however, the preclinical data in this case have been compelling, and we are poised to activate a CDH17-directed CAR T-cell trial that includes patients with NETs. So, we shall see.

First, just to touch briefly on the progress that has been made in advanced pancreatic NETs, the combination of capecitabine and temozolomide was shown to be effective in the practice-confirming ECOG-ACRIN E2211 study. These were patients with low- or intermediate-grade disease and progression within the last 12 months, and now we have level 1 evidence showing high rates of response and impressive survival outcomes. An Alliance for Clinical Trials in Oncology study will compare lutetium Lu 177 dotatate with capecitabine plus temozolomide in the third-line setting after progression on SSA therapy (NCT05247905). Additionally, cabozantinib is being studied in the CABINET trial, led by Jennifer A. Chan, MD, MPH (NCT03375320). CABINET is exploring cabozantinib vs placebo in advanced NETs of a number of different origins, including the small bowel, pancreas, and lung. Sunitinib and everolimus are FDA approved for pancreatic NETs, everolimus is approved for nonfunctional small-bowel NETs, and there is ongoing research on other kinase inhibitors as well. 

With the small-bowel NETs that are typically associated with carcinoid syndrome, the landscape is somewhat different, and kinase inhibitors have less of a role. Regarding telotristat, my belief is that it may actually be more effective against syndromic diarrhea than is apparent from the TELESTAR trial, which showed a significant, but very modest, reduction in diarrhea symptoms. It is not clear to me that diarrhea due to other causes was rigorously excluded in that trial; in my experience, telotristat works quite well in patients whose diarrhea is truly from carcinoid syndrome. It is important to exclude other common causes of diarrhea, such as diarrhea from bile acid malabsorption and steatorrhea from SSA therapy.

I agree that these are exciting times in NET research. PRRT with beta-particle emitters truly has been at the forefront, and now there is also excitement about targeted alpha-particle therapy. We will be very interested to learn whether targeted alpha therapy might be more effective, might provide more syndromic control, and might be less toxic than beta-emitting therapy, perhaps with a lower, long-term risk of leukemia.

The ACTION-1 study using actinium-225 (²²⁵Ac)–DOTATATE is open for patients with progressive gastroenteropancreatic NETs who have previously received lutetium PRRT (NCT05477576), and there are active and soon-to-be-active trials using lead-212 (²¹²Pb) PRRT. I think that the next front is going to be PRRT given together with some other agent. An immunotherapy approach with PRRT is one possibility, and there are thoughts of combining PRRT with poly (ADP-ribose) polymerase inhibitors in higher-grade tumors, although the leukemia risk is a concern. However, I do think that we need to be identifying and developing new NET targets.

As my colleagues alluded to, there are several newer PRRT strategies that are in development for patients with NETs. Alpha emitters emit larger particles than the beta emitters (eg, lutetium-177 and yttrium). As a result, the alpha emitters may be more cytotoxic with less so-called collateral damage to surrounding tissue. Preliminary evidence from prospective trials of the alpha emitters ²²⁵Ac-DOTATATE and ²¹²Pb-DOTAMTATE suggests that response rates are higher with the alpha emitters than with the beta emitters.

Additionally, at Moffitt Cancer Center, we have also been working preclinically on a CAR T-cell molecule that targets the somatostatin receptor (SSTR) using an SSA, and we are working on bispecific molecules using somatostatin as a target for the SSTR. 

Another novel target is HIF-2α. Belzutifan, an HIF-2α inhibitor, is FDA approved for von Hippel-Lindau (VHL) syndrome, an autosomal dominant hereditary disease that can cause renal cell carcinoma and pancreatic NETs, among other neoplasms. We have seen a VHL syndrome patient with a metastatic pancreatic NET who had a complete response to belzutifan. Clearly, metastatic pancreatic NETs in VHL syndrome are very rare; however, there is now interest in studying belzutifan in sporadic pancreatic NETs that are not associated with VHL syndrome.