<p>Optimal treatment sequencing for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is currently difficult to determine due to limited data, so it is unclear where PRRT best fits. A presentation at the recent <strong>2025 Society of Nuclear Medicine & Molecular Imaging (SNMMI) Annual Meeting</strong> reviewed and discussed currently available data.</p> <p><br></p> <p><em>Following this presentation, featured expert Jonathan R. Strosberg, MD, was interviewed by </em>Conference Reporter<em> Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Strosberg on these findings are presented here.</em></p>

¹⁷⁷Lu-dotatate has been US Food and Drug Administration (FDA) approved for the treatment of GEP-NETS since 2018 based on the phase 3 NETTER-1 trial. In NETTER-1, as well as in other retrospective trials, ¹⁷⁷Lu-dotatate was typically administered after progression on an SSA. There are other treatment options available, including everolimus and cabozantinib. Hepatic artery embolization is also an option for patients with unresectable liver-dominant disease. Moreover, for pancreatic NETs, we use quite a bit of cytotoxic chemotherapy, most commonly capecitabine and temozolomide. Therefore, it can be hard to know where to sequence PRRT among these treatments.

<br>

The outcomes that we have seen with ¹⁷⁷Lu-dotatate, including median progression-free survival (mPFS), seem to be better than what we have seen with targeted agents such as everolimus or cabozantinib. However, until recently, we had not had high-quality studies that compared ¹⁷⁷Lu-dotatate with active treatments. The very small, randomized, phase 2 OCLURANDOM trial from France compared ¹⁷⁷Lu-octreotate with sunitinib and reported an mPFS of 20.7 months vs 11 months, respectively, but it was not powered for comparison.

<br>

The COMPETE trial was one of the first large phase 3 studies to compare ¹⁷⁷Lu-edotreotide (also known as ¹⁷⁷Lu-DOTATOC) vs everolimus, a standard of care. The mPFS was 23.9 months with ¹⁷⁷Lu-edotreotide vs 14.1 months with everolimus, which was statistically significant. There was a very slight trend toward improved overall survival (OS), although the study was not powered to detect OS differences. This suggests that it may be better to sequence PRRT a little earlier than everolimus, but this does not mean that it is the right strategy for every patient. There are some contraindications; for example, high-burden peritoneal carcinomatosis is a partial contraindication to PRRT.

<br>

How should we sequence PRRT compared with other drugs? The phase 3 NETTER-2 trial looked at first-line PRRT with ¹⁷⁷Lu-dotatate in patients with higher grade 2 and 3 GEP-NETs (ie, a Ki-67 proliferation index of 10%-55%). This Ki-67 index occurs in a minority of NETs, as most GEP-NETs have a lower Ki-67 index. The primary end point of PFS was met with a significant improvement, and the response rate was also quite high with PRRT. In this patient population, it may be a good idea to start with PRRT rather than waiting until progression. The real question when talking about treatment sequencing is: Will a particular sequence improve OS and not just PFS? So far, we have not seen evidence that first-line PRRT improves OS. It is also a riskier treatment than an SSA, so there is some debate as to whether first-line PRRT is always the preferred option for patients with advanced and higher grade 2 and 3 GEP-NETs.

<br>

At the 2025 SNMMI Annual Meeting, Thorvardur R. Halfdanarson, MD, discussed different sequencing scenarios in his presentation titled “Sequencing of Systemic Therapy for NETs – Where Does PRRT Fit In?” Here are my thoughts on some potential different scenarios. For a patient with a grade 2 NET that is not very symptomatic and does not have a very high tumor burden, I would probably start with an SSA and wait until progression before starting PRRT. However, if a patient has a grade 3 symptomatic NET and I do not feel that an SSA would be sufficient to control the disease and/or the symptoms, I think that it would be good to use PRRT first line. For someone with a grade 3 NET who is very sick with a declining performance status and abnormal liver function tests, you might want to prescribe chemotherapy and have them start it the next day because they may not be able to wait to start PRRT.

<br>

What makes sequencing more complicated, especially for patients with pancreatic NETs, is that the disease can transform over time. You may start with ¹⁷⁷Lu-dotatate followed by chemotherapy, but the disease may transform after several years, and everolimus, sunitinib, or cabozantinib are unlikely to be very effective. In this case, you probably need to use a platinum-based chemotherapy option next. So, it is not always just a question of going from drug A to D in a linear fashion.