NETs Year in Review: RLT Advances as Combo Strategies and ICIs Show Limited Benefit

The past year in neuroendocrine neoplasms (NENs) brought new radioligand therapy (RLT) options and a wave of translational work aimed at better classifying these diseases, while combination strategies and checkpoint inhibitors largely failed to deliver, according to Arvind N. Dasari, MD, MS, professor at The University of Texas MD Anderson Cancer Center, who gave the NET Year in Review presentation at the 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium.¹

Dasari organized the review around 3 areas: epidemiology, translational research, and clinical trials.

Rising Incidence and the Question of Rarity

The incidence of NENs continues to rise, driven largely by early-stage, low-grade disease. In a population-based dataset from Ontario, Canada, the incidence of gastroenteropancreatic NENs increased from 1.83 to 7.46 per 100,000, with nearly all of the growth in nonmetastatic disease while the incidence of metastatic disease remained largely flat.

Dasari noted that this pattern, in which overall incidence rises while metastatic incidence and mortality stay stagnant, has been described as a signature of overdiagnosis in other cancers, such as thyroid and kidney cancer.

The rising numbers also raise the question of whether NENs should still be considered rare. Definitions of rare cancers vary by region and can be based on incidence or prevalence, and prevalence estimates change depending on how far back they look. Dasari explained that the distinction matters for drug development, because the FDA provides regulatory incentives for rare indications, including biologically defined subsets of more common cancers.

"I don't have answers to these questions," Dasari said.

Translational Research Refines Classification

Dasari highlighted a series of studies that are reshaping understanding of NEN biology. Multiomic work suggested that small bowel NETs arise from enteroendocrine progenitor states driven by epigenetic mechanisms, and spatial transcriptomic studies identified distinct tumor cell programs and subtypes whose behavior is shaped by local interactions with the tumor microenvironment. In pancreatic NETs, a malignant cell state associated with worse prognosis and macrophage-derived glutamate signaling was identified as a potential therapeutic target.

Other studies focused on classification. Deep molecular profiling of lung NETs identified a fourth molecular group, termed supra-carcinoids, that had the worst long-term survival, and investigators developed an immunohistochemistry and deep learning classifier to make the grouping usable in the clinic. A proteomic analysis of neuroendocrine carcinomas (NECs) from 26 anatomic sites defined 5 subtypes, including an inflamed subtype associated with better survival and benefit from immunotherapy.

In gastroenteropancreatic NENs, delta-like ligand 3 (DLL3) was expressed in most NECs but rarely in grade 1 or 2 NETs, and DLL3-directed immuno-PET imaging showed potential for selecting patients for DLL3-targeted therapies.² A functional assay for SDHB variants also reclassified most variants of uncertain significance, which can guide surveillance and family testing in hereditary pheochromocytoma and paraganglioma (PPGL).

"Those efforts are ongoing, but by no means are these ready for prime time," Dasari said, noting that substantial validation work remains before these classification approaches enter clinical use.

Radioligand Therapy Continues to Expand

Dasari described the role of peptide receptor radionuclide therapy (PRRT) as continuing to expand, with earlier use and more radioligand options. Preplanned and post hoc analyses of the phase 3 NETTER-2 trial (NCT03972488) showed that the benefit of first-line lutetium Lu 177 dotatate (Lutathera) plus octreotide was consistent across tumor grade, primary site, and somatostatin receptor uptake subgroups.³

The phase 3 COMPETE trial (NCT03049189) compared lutetium Lu 177 edotreotide, a synthetic ligand with high affinity for somatostatin receptors 2 and 5, with everolimus in patients with grade 1 or 2 gastroenteropancreatic NETs, making it one of the first RLT trials with an active control arm.⁴ Lutetium Lu 177 edotreotide significantly improved progression-free survival (PFS) (HR, 0.67; 95% CI, 0.48-0.95; P = .022). Dasari noted that the FDA issued a complete response letter, but that it raised no concerns about study design or efficacy, so approval appears delayed rather than denied.

A second no-carrier-added lutetium Lu 177 dotatate product also replicated the PFS benefit of PRRT over high-dose octreotide in a phase 3 trial, although longer follow-up is needed to assess myelodysplastic syndrome and renal toxicity. With several lutetium Lu 177 dotatate products now approved or pending, Dasari said access and pricing may improve, although labels and indications differ.

Alpha-emitter therapy is also advancing. A phase 1/2 trial of a lead 212-based PRRT in PRRT-naive, somatostatin receptor 2-positive NETs showed activity and tolerability, and the phase 3 ACTION-1 trial (NCT05477576), which compared an actinium 225-based agent with investigator's choice of therapy in patients who progressed after lutetium Lu 177 PRRT, reported positive topline results.

Combinations and Targeted Therapies Have Yet to Add Benefit

In contrast, attempts to improve on PRRT with combination therapy were largely unsuccessful. Adding capecitabine to lutetium Lu 177 dotatate did not improve efficacy and lowered quality-adjusted life-years, and a trial of PRRT plus capecitabine and temozolomide did not meet its primary end point in either the pancreatic or small bowel NET cohort. A pilot study of pembrolizumab plus PRRT showed responses but was associated with immune-related diabetes, and a phase 1 study of triapine as a radiosensitizer has moved into a randomized phase 2 trial.

Among targeted therapies, vascular endothelial growth factor tyrosine kinase inhibitors continue to show class activity in NETs. In the phase 3 AXINET trial (NCT01744249), axitinib plus octreotide improved response rates in extrapancreatic NETs, but the primary end point of investigator-assessed PFS was not met.⁵ Separate phase 2 studies of cabozantinib combined with nivolumab or with temozolomide showed limited activity. Treatment sequencing also remains unresolved, as a randomized trial of streptozocin plus fluorouracil and everolimus in pancreatic NETs found that neither sequence was superior for PFS.

Dasari also highlighted belzutifan, an oral hypoxia-inducible factor 2-alpha inhibitor that was approved for advanced PPGL based on durable disease control in a phase 2 trial, and an expert consensus statement on incretin mimetics in patients with NENs that recommends avoiding these agents in patients with medullary thyroid cancer, multiple endocrine neoplasia type 2, or insulinoma.⁶

Checkpoint Inhibitors Disappoint in NEC, but New Targets Emerge

In NEC, unselected use of checkpoint inhibitors showed limited activity. The randomized phase 2 NIPINEC trial (NCT03591731) of nivolumab with or without ipilimumab in pretreated advanced NEC did not meet its primary end point, and outcomes were particularly poor in patients with gastroenteropancreatic NEC.⁷ Cohorts evaluating cabozantinib plus atezolizumab and cabozantinib plus nivolumab and ipilimumab in high-grade NENs were stopped for lack of efficacy.

Dasari pointed to recent positive phase 3 trials of DLL3- and B7-H3-directed agents in small cell lung cancer as a model for extrapulmonary NEC.

"There were positive [phase 3] trials in small [cell lung] cancer that are sure to change the treatment paradigm there, and I think have a lot of relevance for us as well," Dasari said.

Early data presented at the 2026 American Society of Clinical Oncology Annual Meeting and the 2026 European Society for Medical Oncology Congress showed activity for DLL3-directed T-cell engagers, a CD56-directed antibody-drug conjugate, and bispecific antibodies targeting programmed death-ligand 1 in NEC, although randomized data are still needed.

References

1. Dasari AN. NET year in review. Presented at: 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium; November 5-7, 2026; Las Vegas, NV.

2. Thummalapalli R, Tendler S, Chou JF, et al. Delta-like ligand 3 expression and functional imaging in gastroenteropancreatic neuroendocrine neoplasms. JCO Precis Oncol. 2025;9:e2500724.

3. Ferone D, Pavel M, Herrmann K, et al. [¹⁷⁷Lu]Lu-DOTA-TATE plus long-acting octreotide in patients with newly diagnosed, advanced, grade 2-3, gastroenteropancreatic neuroendocrine tumours: preplanned and post-hoc efficacy analyses from the randomised, phase 3 NETTER-2 trial. EClinicalMedicine. 2026;98:104109.

4. Walter T, Jann H, Ansquer C, et al. [¹⁷⁷Lu]Lu-edotreotide versus everolimus for gastroenteropancreatic neuroendocrine tumours (COMPETE): a phase 3, multicentre, randomised, open-label, superiority trial. Lancet. 2026;408(10551):234-247.

5. Garcia-Carbonero R, Benavent M, Jimenez-Fonseca P, et al. Axitinib and long-acting octreotide in advanced extrapancreatic neuroendocrine tumors: a randomized, double-blind, placebo-controlled, phase III clinical trial (AXINET, GETNE 1107). J Clin Oncol. 2026;44(9):774-786.

6. Grewal US, Ear PH, Sonbol MB, et al. Practical considerations for the use of incretin mimetics in patients with neuroendocrine neoplasms: an expert consensus statement. Cancer. 2026;132(16):e70586.

7. Walter T, Mazieres J, Otto J, et al. Nivolumab ± ipilimumab in patients with pretreated advanced neuroendocrine carcinoma: the GCO-001 NIPINEC randomized phase II trial. J Clin Oncol. 2026;44(12):1120-1129. doi:10.1200/JCO-25-01657