Additional Advances in Neuroendocrine Tumor Research and Clinical Trials With Aman Chauhan, MD

The treatment landscape for neuroendocrine tumors (NETs) is undergoing a period of accelerated progress, with new epidemiologic insights, targeted therapies, and novel immunotherapeutic approaches reshaping clinical practice. Aman Chauhan, MD, Associate Professor of Clinical Medicine at the University of California, San Francisco (UCSF), recently chaired i3 Health’s CME activity, Optimizing Neuroendocrine Tumor Outcomes: Closing the Gaps in Diagnosis and Care. With several important developments emerging in recent months, Dr. Chauhan shared key updates that are influencing how clinicians approach the treatment of NETs.

Rising Incidence and Expanding Treatment Options

One of the most notable updates in the field is epidemiologic. Recent analyses of national cancer databases, including work from MD Anderson and UCSF, demonstrate that the incidence of neuroendocrine cancers in the United States has surpassed 8 per 100,000.  “NETs are considered a rare disease, but this suggests that maybe NETs are not so rare anymore,” Dr. Chauhan noted. This rising burden reinforces the need for expanded research efforts and clinical trial development. 

On the therapeutic front, subgroup analyses from the CABINET trial have provided meaningful data for patients with lung NETs—an area historically lacking robust evidence. Nearly one-quarter of CABINET participants had thoracic NETs, including lung and thymic primaries. In this subgroup, cabozantinib significantly improved median progression-free survival (PFS), extending it to approximately 8 months compared with 2.7 months in the control arm. “The data looks very promising, so that has been an important recent update in the NETs world.” Dr. Chauhan noted. With FDA approval of cabozantinib for advanced progressive NETs regardless of primary site, these findings offer much-needed evidence-based guidance for thoracic disease.

Advances in High-Grade Neuroendocrine Carcinoma

High-grade neuroendocrine carcinoma (NEC) remains an area of profound unmet need, with limited therapeutic progress over decades. However, emerging data from the DAREON clinical trial series are generating optimism. These studies evaluate obrixtamig, a DLL3-targeted T-cell engager, in patients with high-grade NEC.

Updated phase 1 and 2 data from DAREON-5 and DAREON-7, presented at recent international meetings, demonstrate promising activity and manageable safety profiles. “It’s been very promising to see great activity and safety of this DLL3-targeted T-cell engager,” said Dr. Chauhan. “We await a registrational phase 3 study to enroll, read out, and hopefully lead to a new treatment option for our high-grade patients.”

In parallel, cooperative group research is also underway. A SWOG study is evaluating the addition of immunotherapy to frontline chemotherapy for high-grade NEC, signaling broader efforts to modernize treatment in this aggressive subtype.

Innovations in Radiopharmaceuticals and Immunotherapy

Radiopharmaceutical therapy continues to evolve beyond established peptide receptor radionuclide therapy (PRRT). Dr. Chauhan is involved in a National Cancer Institute (NCI)–sponsored phase 1 study combining lutetium Lu 177 dotatate with peposertib, a DNA protein kinase inhibitor designed to act as a radiation sensitizer. “Our hope is that with a combination of this very precise radiation sensitizer, we will be able to enhance the efficacy of PRRT while maintaining safety,” he explained.

Additionally, Dr. Chauhan and colleagues are conducting a first-in-human phase 1 trial combining an oncolytic virus with dual immune checkpoint blockade—ipilimumab and nivolumab. The oncolytic virus is engineered to selectively target neuroendocrine cancer cells, potentially augmenting immunotherapy responses. Interim data are forthcoming, reflecting the expanding role of immunomodulatory strategies in NETs.

The Imperative of Multidisciplinary Care

Given the heterogeneity of NETs, multidisciplinary collaboration remains foundational to optimal care. Differences in pathology—such as typical versus atypical carcinoid, and grade 3 NET versus NEC—can dramatically alter management. Nuclear medicine input is essential for assessing somatostatin receptor expression and determining PRRT candidacy, while interventional radiology expertise guides the use of liver-directed therapies, including embolization, ablation, and newer noninvasive modalities like histotripsy.

“No two NET patients are alike,” Dr. Chauhan emphasized. “It’s highly important to engage a multidisciplinary team. At our center, we have a multidisciplinary tumor board where we present cases to colleagues from surgery, interventional radiology, nuclear medicine, and pathology, just to name a few. If we don’t discuss these cases in a multidisciplinary setting, we would not get all those expert opinions and truly would not do justice to patients.” 

Looking Ahead: Incremental Gains and Transformative Potential

For well-differentiated NETs, incremental improvements continue to build upon progress made over the past decade. Ongoing studies are evaluating oral and next-generation somatostatin analogs, radiation-sensitizing combinations, and alpha-emitting PRRT agents.

For high-grade NEC, the outlook is particularly hopeful. “This is an area where we have made very little progress in the last 50 years, but finally, there may be some light at the end of the tunnel,” Dr. Chauhan said. “We have some very important clinical trials that are currently undergoing in the US and internationally.”

The Importance of Advocacy and Awareness

As Rare Disease Day underscores the challenges of uncommon cancers, Dr. Chauhan highlighted the role of sustained advocacy in driving innovation. The substantial progress seen in recent years is, in part, a result of coordinated efforts among clinicians, researchers, patient advocacy groups, and industry partners. 

“It’s very important to continue to raise awareness about this disease,” he underscored. “We have to allocate resources towards studying it better and developing clinical trials. I’m very happy to tell you that over the last seven to 10 years, there have been seismic changes in drug development, and that was possible because of continued advocacy. We need continued support from all stakeholders—federal government, professional societies, patient support groups, and industry sponsors—to chime in, work hard, and continue to make incremental improvements.” 

Key Takeaways

• Rising Incidence: The US incidence of NETs has surpassed 8 per 100,000, underscoring a growing disease burden and the need for expanded research efforts.

• Lung NET Data: CABINET subgroup analyses demonstrate significant PFS benefit with cabozantinib in thoracic NETs, supporting its use across primary sites.

• High-Grade NEC Innovation: DLL3-targeted T-cell engager therapy (obrixtamig) and frontline chemo-immunotherapy trials represent promising strategies in a historically treatment-resistant population.

• Radiopharmaceutical Evolution: Combination strategies with radiation sensitizers and emerging alpha-PRRT approaches may enhance the efficacy of established PRRT therapies.

• Multidisciplinary Coordination: Pathology, nuclear medicine, interventional radiology, and surgical collaboration are critical to optimizing individualized treatment pathways for NET patients.

About Dr. Chauhan

Aman Chauhan, MD, is an Associate Professor of Clinical Medicine at the University of California, San Francisco. He specializes in the treatment of neuroendocrine cancers, including carcinoid tumors, high-grade neuroendocrine carcinomas, and small and large cell neuroendocrine carcinoma. He is a national principal investigator of several neuroendocrine cancer trials, and his research focuses on the use of theranostics to develop novel treatment and management strategies for these diseases.