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Neuroendocrine Tumor Clinical Trial Landscape

Track NETs, carcinoid, and neuroendocrine carcinoma trials in 2026. Active programs include Exelixis's zanzalintinib vs. everolimus Phase 2/3, multiple lutetium DOTATATE retreatment and intensification trials, and novel DLL3 bispecific and complement inhibitor studies. Get daily alerts for new and updated trials.

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Key Active Programs in Neuroendocrine Tumors (2026)

NCT IDDrug / MechanismSponsorPhaseStatus
NCT06943755 Zanzalintinib (XL092) vs. everolimus — non-pancreatic NETs Exelixis Phase 2/3 Recruiting
NCT07037420 ALXN2420 (complement factor D inhibitor) + SSA Alexion/AstraZeneca Phase 2 Recruiting
NCT06788938 Tarlatamab (DLL3 BiTE) in DLL3+ NETs Jonsson/UCLA Phase 2 Recruiting
NCT05773274 177Lu-DOTATATE retreatment vs. standard of care NCI Phase 2 Recruiting
NCT06955169 177Lu-DOTATATE vs. standard of care (RTOG) RTOG Foundation Phase 2 Recruiting
NCT05746208 Lenvatinib + pembrolizumab in well-differentiated G3 NETs UCSF Phase 2 Recruiting
NCT06161532 Sacituzumab govitecan ± atezolizumab in NETs NCI Phase 2 Recruiting
NCT04665739 177Lu-DOTATATE in somatostatin receptor-positive NETs NCI Phase 2 Recruiting
NCT05058651 177Lu-DOTATATE + atezolizumab combination NCI Phase 2/3 Recruiting
NCT00569127 Octreotide + interferon alfa-2b vs. bevacizumab NCI Phase 3 Active, not recruiting

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The NET Treatment Landscape in 2026

Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies arising from neuroendocrine cells throughout the body — most commonly the gastrointestinal tract (midgut/hindgut), pancreas, and lung. Classification is based on differentiation (well vs. poorly differentiated) and proliferation grade (G1: Ki-67 <3%, G2: Ki-67 3–20%, G3: Ki-67 >20%), with well-differentiated grade 3 NETs representing a distinct biology from poorly differentiated neuroendocrine carcinomas (NECs, the SCLC-like entity).

The Four Lines of NET Therapy

Key Research Questions in NET Trials (2026)

Can zanzalintinib replace everolimus as second-line standard?

Everolimus has significant limitations as second-line NET therapy: response rates of only 5% (though disease stabilization is meaningful), class-effect metabolic toxicities (hyperglycemia, immunosuppression), and modest PFS improvement over placebo (11 months vs. 3.9 months in non-pNETs, RADIANT-4). Zanzalintinib targets VEGFR2, MET, AXL, and MERTK — a broader anti-angiogenic and anti-immune-suppressive profile than everolimus's mTOR inhibition. The Exelixis Phase 2/3 trial (NCT06943755) is the first prospective head-to-head comparison of a multi-kinase inhibitor versus everolimus in non-pancreatic NETs. If zanzalintinib shows superior PFS with manageable toxicity, it could displace everolimus in the second-line setting — a critical commercial opportunity for Exelixis.

What happens after Lutathera — can PRRT be retreated?

Lutetium-177 DOTATATE (Lutathera) is administered as 4 fixed cycles of 7.4 GBq every 8 weeks. After completing 4 cycles, a significant proportion of patients respond and maintain disease control, but eventually progress. The standard Lutathera protocol has no defined retreatment pathway. Two active NCI trials (NCT05773274 comparing retreatment vs. standard care; NCT04665739 exploring PRRT in broader populations) are generating data on retreatment feasibility, optimal timing, and cumulative renal/bone marrow dosimetry limits. These trials are critical for establishing evidence-based post-Lutathera pathways, which currently rely entirely on physician judgment and compassionate use.

DLL3 targeting: from SCLC to high-grade NETs

DLL3 is a Notch inhibitory ligand with very limited expression in normal adult tissues but high expression in neuroendocrine cancers — including SCLC (70–80%), large-cell neuroendocrine carcinoma (LCNEC), and high-grade extrapulmonary NETs. Tarlatamab's approval in SCLC (DeLLphi-301) opened the door to studying DLL3-targeting in the broader neuroendocrine carcinoma spectrum. The UCLA basket trial (NCT06788938) could expand tarlatamab's label if DLL3-positive high-grade NETs show response rates comparable to SCLC (~40% ORR in second-line). The key unknowns: DLL3 expression frequency in low-grade well-differentiated NETs (likely low) and whether the BiTE mechanism can overcome the immunosuppressive NET tumor microenvironment.

FAQ

Frequently asked questions

What is the zanzalintinib vs. everolimus trial (NCT06943755) and why does it matter for NET?
Zanzalintinib (XL092), an oral multi-kinase inhibitor from Exelixis targeting VEGFR, MET, AXL, and MERTK, is being compared to everolimus in the Phase 2/3 STELLAR-311 trial (NCT06943755) in patients with previously treated neuroendocrine tumors. This matters because everolimus (Afinitor, Novartis) is the standard second-line mTOR inhibitor for non-pancreatic NETs after somatostatin analog failure. If zanzalintinib outperforms everolimus, it would establish a new second-line option in a population where efficacy improvements have been hard to achieve. The trial is actively recruiting as of 2026.
What does PRRT retreatment research test that isn't already known about lutetium-177 DOTATATE?
Lutetium-177 DOTATATE (Lutathera, Advanced Accelerator Applications/Novartis) is FDA-approved for somatostatin receptor-positive gastroenteropancreatic NETs, based on the NETTER-1 trial, which showed a significant progression-free survival benefit versus high-dose octreotide LAR. A key open question is what happens after a patient completes the standard 4 cycles: can the drug be given again once a patient progresses. The NCI-sponsored NET RETREAT trial (NCT05773274) directly tests retreatment with 177Lu-DOTATATE against standard care (everolimus, sunitinib, or cabozantinib) in patients who progressed after prior PRRT (peptide receptor radionuclide therapy). Retreatment feasibility and optimal dosing intervals are among the most active questions in the PRRT field.
What is tarlatamab and why is it being tested in NETs (NCT06788938)?
Tarlatamab (AMG 757) is Amgen's DLL3-targeted BiTE (bispecific T-cell engager), approved in 2024 for small cell lung cancer (SCLC) based on the DeLLphi-301 trial. DLL3 (Delta-like ligand 3) is a Notch pathway inhibitory ligand highly expressed on neuroendocrine cancers, including not just SCLC but also large-cell neuroendocrine carcinoma (LCNEC), high-grade pulmonary NETs, and DLL3-expressing extrapulmonary neuroendocrine carcinomas. The UCLA Phase 2 basket trial (NCT06788938), run through the Jonsson Comprehensive Cancer Center, evaluates tarlatamab in advanced DLL3-expressing tumors beyond SCLC, including high-grade NETs and neuroendocrine carcinomas where DLL3 expression is confirmed by immunohistochemistry (IHC). This basket study could expand tarlatamab's use well beyond SCLC if NETs show response rates comparable to small cell lung cancer.
What are approved treatments for NETs in 2026 and where do clinical trials fit?
Approved NET therapies in 2026 include: somatostatin analogs (octreotide LAR, lanreotide) for somatostatin receptor (SSR)-positive functional and non-functional NETs; everolimus (Afinitor) for progressive, non-functional, well-differentiated NETs of GI or lung origin and for pancreatic NETs; sunitinib (Sutent) for progressive, well-differentiated pancreatic NETs; lutetium-177 DOTATATE (Lutathera) for SSR-positive GEP-NETs (NETTER-1); and telotristat ethyl (Xermelo) for carcinoid syndrome diarrhea inadequately controlled on somatostatin analogs. Clinical trials are most active in the post-SSA, post-everolimus setting; high-grade NETs and neuroendocrine carcinomas (tarlatamab); PRRT intensification and retreatment; and novel targeted therapies.
What is the difference between a carcinoid tumor and a neuroendocrine tumor?
"Carcinoid" is an older term historically applied to well-differentiated NETs of the GI tract and lung. Current classification prefers "neuroendocrine tumor" (NET) graded G1 through G3, with "carcinoid" retained as an informal descriptor for clinical context. In modern clinical trials, "carcinoid" and "well-differentiated NET" are largely interchangeable for G1-G2 GI/lung NETs. High-grade tumors are called neuroendocrine carcinomas (NEC): these behave like SCLC and are treated differently from well-differentiated NETs. Clinical trial eligibility typically specifies the Ki-67 grade and differentiation status to ensure the right patient population.
What is the difference between DataLookout and a ClinicalTrials.gov search for "neuroendocrine"?
A ClinicalTrials.gov search for "neuroendocrine" returns hundreds of studies, including observational studies, biomarker collection studies, completed trials, and single-center Phase 1 dose-escalation studies. DataLookout's daily digest can be filtered to actively recruiting Phase 2 and Phase 3 industry and academic trials, the ones where NET patients can actually sign up. You can set alerts specifically for "neuroendocrine" trials and receive notification when zanzalintinib opens new sites, when the tarlatamab basket trial updates enrollment criteria, or when a new PRRT intensification study launches.

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Related Pages

Live trial data Data as of 2026-08-28, ClinicalTrials.gov

287 active trials, 171 recruiting. Phases: Early Phase 1: 9, Phase 1: 65, Phase 2: 121, Phase 3: 25, Phase 4: 6.

Top sponsorTrials
Novartis Pharmaceuticals6
Suzhou Zelgen Biopharmaceuticals Co.,Ltd5
Merck (MSD)3
Exelixis2
Crinetics Pharmaceuticals Inc.2

View the full sponsor pipeline on the dashboard

Notable trials Ranked by recent tracked changes, ClinicalTrials.gov data as of 2026-08-28
TrialStatusLatest tracked changeSeen
Study of PRRT in Metastatic, WHO Grade 1 or 2, SSTR Positive, GEP-NET Who Are… NCT04609592Active, Not RecruitingCompletion moved earlier: 2027-09 → 2027-052026-08-13
Safety/Efficacy Study of CID-078 in Patients With Advanced Solid Tumor… NCT06577987Active, Not RecruitingEnrollment closed, study ongoing2026-08-27
Zanzalintinib Versus Everolimus in Participants With Locally Advanced or… NCT06943755RecruitingTrial sites expanded: 120 → 124 locations2026-08-27
A First-in-human (FIH), Phase 1 Study of ML261, an Autologous Potency Enhanced… NCT07488923RecruitingRecruitment opened2026-08-26
Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid… NCT02568267Active, Not RecruitingTrial sites reduced: 130 → 120 locations2026-08-26

Each trial page shows every change DataLookout has recorded for that trial.

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