GEP-NET–Focused Research Refines Optimal PRRT Use in Well-Differentiated Disease

Evolving research in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) highlights the growing importance of Lutetium Lu 177 dotatate (Lutathera) in earlier treatment lines and underscores how tumor differentiation guides personalized therapeutic decision-making, according to Rohit Thummalapalli, MD.

“Some new, exciting clinical trials have been completed in the past 2 years in the NET setting,” Thummalapalli said in an interview with OncLive®.

In the interview, Thummalapalli discussed the current treatment paradigm for patients with GEP-NETs, focusing on the expanding role of Lutetium Lu 177 dotatate across lines of therapy. He also explained the importance of considering the degrees of differentiation and mitotic activity in individual tumors to determine optimal treatment strategies for patients with well-differentiated disease.

Thummalapalli is an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive: What recent research has helped expand the NET treatment paradigm?

Thummalapalli: [The phase 3 NETTER-2] trial [NCT03972488] was for Lutetium Lu 177 dotatate for the first-line treatment of patients with high-risk GEP-NETs. The phase 3 CABINET study [NCT03375320] led to the FDA approval of cabozantinib [Cabometyx] for the treatment of advanced, treatment-refractory NETs.

How does pathologic grade influence treatment decision-making for GEP-NETs?

For both pancreatic and extrapancreatic NETs, [if they are] well differentiated, the degree of differentiation and mitotic activity is important when deciding how to treat these patients. We think about grade 1, 2, and 3 tumors based on Ki-67 index and mitotic activity. These are likely progressive in terms of disease aggressiveness.

Up until a few years ago [with the introduction of] the 2019 World Health Organization criteria, we had not been able to distinguish between high-grade, well-differentiated NETs and poorly differentiated neuroendocrine carcinomas. A relatively recent distinction that we’ve made is that there is a disease entity that is high-grade, well-differentiated NETs. We don’t have a lot of randomized clinical trial data informing us on how care for these patients. NETTER-2 was the first randomized clinical trial that at least partially informs a new treatment option for patients with grade 2 or grade 3 well-differentiated NETs.

What clinical trial data drove the FDA approval of Lutetium Lu 177 dotatate for the treatment of patients with GEP-NETs?

Lutetium Lu 177 dotatate was initially approved based on findings from the [phase 3] NETTER-1 study [NCT01578239]. Patients with midgut NETs who were somatostatin receptor [SSTR] avid with prior progression of disease on octreotide somatostatin analog therapy were randomly assigned to receive Lutetium Lu 177 dotatate vs high-dose octreotide. [Findings from] NETTER-1 showed a significant improvement in progression-free survival [PFS] for patients in the Lutetium Lu 177 dotatate arm, leading to the FDA approval of this peptide receptor radionuclide therapy [PRRT] for patients with prior progression on octreotide-based therapy. There has not been a statistically significant improvement in overall survival [OS] in NETTER-1, but this is likely confounded by a high percentage of patients who crossed over from the control arm to the PRRT arm at progression.

Up until NETTER-2, the approval for this PRRT was mainly restricted to patients who had previously developed progression of disease on somatostatin analog therapies. However, the NETTER-2 data evaluated patients with grade 2 and grade 3 disease, were SSTR avid, and were treatment naive. [NETTER-2 randomly assigned these] patients to receive PRRT [with Lutetium Lu 177 dotatate] or high-dose octreotide. In this population, [the trial] showed a significant PFS benefit with Lutetium Lu 177 dotatate. This [agent] has now been incorporated into [the National Comprehensive Cancer Network] guidelines [for the treatment of neuroendocrine and adrenal tumors] as a level 2A indication [for patients with locoregional advanced and/or distant metastatic gastrointestinal NETs in the first-line setting].¹

OS [data from NETTER-2] remain immature at this point, so we are looking forward to future updates to see if there is a demonstrable OS benefit with this intervention. But at least in our practice, we have been comfortable offering and using first-line PRRT for a selected patient population, particularly patients with high tumor bulk who are symptomatic from disease, because there was a promising overall response rate in the PRRT arm [of NETTER-2] of [43.0% (95% CI, 35.0%-51.3%)].² We have not seen [this efficacy with] other agents for this disease subgroup.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Neuroendocrine and adrenal tumors, version 3.2025. Accessed November 4, 2025. https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf
2. Singh S, Halperin D, Myrehaug S, et al. [177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: primary analysis of the phase 3 randomized NETTER-2 study. J Clin Oncol. 2024(suppl 3):LBA588. doi:10.1200/JCO.2024.42.3_suppl.LBA588
3. Lutathera. Prescribing information. Novartis; 2024. Accessed November 4, 2025. https://www.novartis.com/us-en/sites/novartis_us/files/lutathera.pdf