The treatment landscape for neuroendocrine tumors (NETs) is rapidly evolving. From the recent FDA approval of cabozantinib to growing evidence supporting earlier use of peptide receptor radionuclide therapy (PRRT), and the development of next-generation alpha-emitter radioligand therapies, new strategies are reshaping how clinicians approach both well-differentiated NETs and aggressive neuroendocrine carcinomas. At the 2026 Hawaii Gastrointestinal Cancers Summit, Dr. David Zhen provided a comprehensive update on emerging systemic therapies, sequencing considerations, and promising novel agents that may soon expand options for patients with gastrointestinal neuroendocrine malignancies.

Dr. David Zhen is a medical oncologist and assistant professor of medicine at the University of Washington, specializing in gastrointestinal cancers with a clinical interest in cancers of the stomach, esophagus, and pancreas. His research is a collaborative endeavor between Fred Hutch and the University of Washington. At the 2026 Hawaii Gastrointestinal Cancers Summit, Dr. Zhen presented a comprehensive update on the evolving treatment landscape for neuroendocrine tumors (NETs) and neuroendocrine carcinomas, covering guideline changes, emerging systemic therapies, sequencing strategies for radioligand therapy, next-generation alpha emitters, and novel agents on the horizon.

The transcript report below has not been reviewed by the speaker and may contain errors.

Take-Home Message

1. Cabozantinib is an approved, effective treatment option for previouslytreated NET.
2. Moving radioligand therapy/PRRT earlier in the disease course may be moreeffective compared to other targeted agents.
3. Alpha-emitter radioligand therapy may become an available treatment forGEP-NET in the future.
4. Enroll patients with GEP-NET in clinical trials when available.

Reassessing Chromogranin A as a Biomarker in Neuroendocrine Tumors

Chromogranin A has long been used as a tumor marker in neuroendocrine tumors, but its reliability has come under increasing scrutiny. Numerous factors can artificially elevate chromogranin A levels independent of disease activity, including proton pump inhibitors, certain medications, and even dietary intake on the day of testing. Clinically, many patients exhibit rising chromogranin A values while remaining symptomatically stable with unchanged imaging. Leaders in the field have revisited the data and reached a clear consensus: chromogranin A is a poor marker that generates confusion for both providers and patients alike. Updated guidelines now recommend against its use for disease monitoring or diagnosis. Although some clinicians have historically used it as a reassuring data point when levels decline, current evidence does not support that practice.

Updated WHO Classification and Evolving Role of Endoscopic Intervention

The 2022 WHO classification update has brought greater attention to the biological heterogeneity of neuroendocrine tumors, reinforcing the importance of distinguishing between indolent and more aggressive disease biology in order to tailor treatment appropriately. Not all neuroendocrine tumors behave the same way, and recognizing this distinction is central to modern management.

Alongside this, expanded use of endoscopy and screening has led to the identification of considerably more stage 1 disease than was seen in prior decades. The role of endoscopic interventions for these early-stage patients has historically been poorly defined, but evolving data now support consideration of endoscopic approaches in carefully selected patients.

The Expanding Systemic Therapy Landscape for GI Neuroendocrine Tumors

The history of systemic therapy for GI neuroendocrine tumors spans several decades. Streptozocin, an older alkylating chemotherapy, has largely been supplanted by temozolomide, which is better tolerated and comparably effective. Subsequent milestones include the approval of octreotide LAR as the first somatostatin analog, followed by everolimus, lanreotide, telotristat for refractory carcinoid syndrome-related diarrhea, and lutetium-177 dotatate (Lutathera), which received FDA approval in 2018. Cabozantinib more recently emerged as a meaningful addition, and ongoing work is now exploring whether treatment with agents in this class might be moved earlier in the disease course rather than reserved for heavily pretreated patients.

Cabozantinib: FDA Approval and Practical Dosing Considerations

Cabozantinib received FDA approval for neuroendocrine tumors in March 2024, making it a newly accessible option in clinical practice. The approval was based on the CABINET study, an NCI trial run through the Alliance group, which enrolled patients in two cohorts: pancreatic neuroendocrine tumors and extra-pancreatic neuroendocrine tumors. The extra-pancreatic cohort is notable because it encompassed tumors outside the GI tract, including lung neuroendocrine tumors and tumors of unknown primary, populations that have been largely underrepresented in clinical trials for a long time. Patients in both cohorts were heavily pretreated, having failed at least two prior systemic therapies not including somatostatin analogs. The primary endpoint was progression-free survival, and both cohorts demonstrated significant improvement.

Tolerability remains a real clinical consideration with cabozantinib. Fatigue, diarrhea, hand-foot syndrome, and hypertension are common adverse effects. In the CABINET study, the starting dose was 60 mg daily, yet two-thirds of patients required a dose reduction to 40 mg. In practice, dosing strategies vary across providers: some begin at 60 mg and reduce upon toxicity, others titrate up from 40 mg, and some initiate and maintain treatment at 40 mg. Clinical experience supports the latter approach, with meaningful responses observed even at the lower dose.

Zanzalintinib and the STELLAR-311 Trial: Moving Targeted Therapy Earlier

Zanzalintinib is a next-generation agent designed along similar mechanistic lines as cabozantinib, with the goals of potentially greater potency and improved tolerability, though the tolerability question remains open based on early data from other tumor types showing overlapping adverse effects. The STELLAR-311 trial is an international study addressing two questions simultaneously: whether zanzalintinib offers advantages over cabozantinib-class therapy, and whether deploying such an agent earlier in the treatment sequence yields greater benefit. The trial enrolls patients with pancreatic or extra-pancreatic neuroendocrine tumors, including lung neuroendocrine tumors and tumors of unknown primary, in the second-line or earlier setting, and randomizes them to zanzalintinib versus everolimus as the control arm. The study is designed with crossover and uses progression-free survival as the primary endpoint, consistent with the methodological standards of the neuroendocrine field.

Next-Generation Somatostatin Analog Formulations

Somatostatin analogs remain foundational in neuroendocrine tumor management, but the current formulations require monthly intramuscular injections administered in a clinical setting. Two emerging approaches aim to improve upon this.

The first is a subcutaneous formulation being evaluated in the SORRENTO trial, which has completed accrual and results are anticipated soon. This agent is administered similarly to low-molecular-weight heparin or other subcutaneous injections and can be self-administered at home. Preclinical data suggest it may also be more potent than octreotide and lanreotide based on absorption characteristics, and it is being compared directly to standard-of-care somatostatin analogs in a randomized design.

The second is an oral somatostatin analog called paltusotine, which is already FDA approved for acromegaly. Clinical data from its development program demonstrated meaningful benefit in controlling carcinoid syndrome symptoms in neuroendocrine tumor patients. Whether paltusotine has direct antitumor activity comparable to injectable somatostatin analogs remains unknown. The phase 3 CAREFRONT study is ongoing and will evaluate both carcinoid syndrome symptom reduction as the primary endpoint and tumor control as a co-endpoint.

Lutathera in the First-Line Setting: Interpreting NETTER-2

The NETTER-2 trial has generated considerable interest and a steady stream of referral questions about whether lutetium-177 dotatate (Lutathera) should be used as first-line treatment. NETTER-2 was designed as a first-line study, enrolling newly diagnosed patients without prior therapy and randomizing them against high-dose octreotide. Several design features merit consideration when interpreting the results. The choice of high-dose octreotide as the comparator is debatable, given that other systemic therapies exist. Additionally, NETTER-2 required patients to be grade 2 or grade 3, in contrast to NETTER-1, which enrolled predominantly grade 1 and 2 well-differentiated small intestinal neuroendocrine tumors. The result is a meaningfully different disease biology population. Given these factors, the improvement in progression-free survival over octreotide, while statistically clear, is not entirely unexpected.

Lutathera is generally well tolerated, but it requires coordinated administration with nuclear medicine or radiology every two months, which is a logistical consideration for patients and care teams. For patients with relatively indolent, low-volume disease, first-line somatostatin analogs remain a reasonable approach. Where upfront Lutathera may be most appropriate is in patients with higher-grade disease, bulky tumor burden, and a need for more active disease control, particularly when concerns about systemic therapy side effects make other options less attractive. Somatostatin analogs stabilize disease effectively but rarely produce meaningful tumor shrinkage, which is a relevant limitation in patients presenting with substantial disease burden.

Sequencing Radioligand Therapy: Evidence from OCTET-Random and COMPETE

The optimal sequence of therapies after progression on somatostatin analogs has been an ongoing question in the neuroendocrine field. Two studies provide relevant, though imperfect, guidance. The OCTET-Random study, presented in 2022, was not a true randomized trial but rather an observational study that compared outcomes in patients who received sunitinib followed by lutetium-177 dotatate versus the reverse sequence. The COMPETE study, reported at the European Neuroendocrine Tumor Society meeting in 2025, addressed the sequencing question more rigorously. Importantly, COMPETE used lutetium-177 edotreotide rather than lutetium-177 dotatate; these agents share the same radionuclide but differ in their chemical linker and are manufactured by different companies.

COMPETE randomized patients who had progressed on prior therapy to either everolimus or lutetium-177 edotreotide. Taken together, both studies suggest that using radioligand therapy earlier in the disease course, before agents such as everolimus or sunitinib, is associated with better progression-free survival. This evidence supports a shift toward earlier deployment of PRRT rather than reserving it for later lines. These findings apply primarily to low-grade disease, and the sequencing question in higher-grade disease, particularly pancreatic neuroendocrine tumors, where temozolomide-based regimens remain highly active, has not yet been definitively addressed.

Alpha Emitters: The Next Frontier in Radioligand Therapy

The currently approved lutetium-177 dotatate is a beta-particle emitter. Beta particles, based on their physical characteristics, are capable of causing single-stranded DNA breaks in cancer cells, which is often sufficient for tumor cell death but can also allow cancer cells to survive and develop resistance. Alpha particles are smaller, carry higher energy, and have a greater likelihood of penetrating the cell nucleus to cause double-stranded DNA breaks, which are considerably harder for cells to repair. Preclinical and early clinical evidence suggest that alpha emitters are more potent than beta emitters, though they are associated with greater toxicity, particularly cytopenias, bone marrow suppression, and renal dysfunction.

Three alpha-emitting agents are currently in advanced clinical investigation. The most near-term readout is expected from the ACTION-1 study, which evaluates actinium-225 dotatate. This trial enrolled patients who had previously received and then progressed on Lutathera, randomizing them to actinium-225 dotatate versus the investigator's choice of systemic therapy. Accrual is complete, though a sub-study requested by the FDA to assess drug pharmacokinetics remains open for enrollment. This trial is considered potentially practice-changing.

The two other agents in development are lead-based alpha emitters: lead-DOTAMTATE and lead-VMT-alphanet, which differ in design and structure. One notable toxicity associated with lead-DOTAMTATE is dysphagia resembling achalasia, which has required management with botulinum toxin injections in some patients. Clinical trials are ongoing for both agents.

Neuroendocrine Carcinomas: Unmet Need and Emerging Therapies

Neuroendocrine carcinomas (NECs), particularly extra-pulmonary NECs, represent a distinct and poorly served population. The standard of care remains platinum plus etoposide, and after progression on this regimen, no established standard of care exists for extra-pulmonary disease. GI-based regimens and combination approaches are used in practice, but outcomes remain poor, and survival is limited.

The role of immunotherapy in extra-pulmonary NECs is also unclear. Unlike small cell lung cancer, where tobacco-related mutagenesis produces a high mutational burden, extra-pulmonary NECs frequently arise in patients without significant smoking history and tend to have lower tumor mutational burden. Whether immunotherapy produces meaningful activity in this setting is not yet established. Nivolumab and ipilimumab have shown responses in some patients in the refractory setting, but predictive biomarkers for response remain elusive. A SWOG-led national study examining the addition of immunotherapy in extra-pulmonary neuroendocrine carcinomas is approximately 80% enrolled and is expected to close accrual and provide data in the coming period.

Novel Agents: Bispecific T Cell Engagers, DLL3-Targeting Strategies, and Antibody-Drug Conjugates

Several novel therapeutic approaches are entering the neuroendocrine carcinoma space. Bispecific T cell engagers and antibody-drug conjugates are both areas of active investigation. DLL3 (delta-like ligand 3) is a target of particular interest. Tarlatamab, already FDA approved for extensive-stage small cell lung cancer, has shown early signals in prostate neuroendocrine carcinomas but has not been a major focus for extra-pulmonary NECs broadly. The agent generating more targeted attention in this space is BI 764532, a DLL3-targeting bispecific made by Boehringer Ingelheim, being evaluated in a series of studies called the DARIEN program. Unlike in small cell lung cancer, where DLL3 expression is near-universally high, DLL3 expression appears more variable in extra-pulmonary NECs and may be predictive of response. Refractory-setting studies are reporting out, and a first-line study in combination with platinum-etoposide is expected to open soon.

An antibody-drug conjugate targeting SEZ6, an antigen associated with neuroendocrine lineage, also showed promising activity at ASCO in a heavily pretreated population, with a waterfall plot demonstrating substantial responses. Progression-free survival and overall survival data are not yet available, but the signal supports continued development of ADC strategies in this disease.

Summary and Key Clinical Takeaways

Cabozantinib is now FDA-approved and should be incorporated into practice for patients with neuroendocrine tumors who have progressed on prior therapies, with dose flexibility at 40 mg being a clinically reasonable and effective approach. Evidence from multiple studies supports moving radioligand therapy earlier in the treatment sequence rather than reserving it for later lines, though this question remains open in higher-grade disease. Alpha emitters represent a promising next step in radioligand therapy, with practice-changing data from the ACTION-1 study anticipated soon. Enrollment in clinical trials, where available, remains strongly encouraged. In a field that for years had few therapeutic advances, the pace of drug development in neuroendocrine tumors and carcinomas has accelerated considerably, and the next several years are expected to bring meaningful new options for patients.