A Turning Point in Neuroendocrine Tumor Treatment: Antiangiogenic Drugs

Neuroendocrine tumors (NETs) are seeing encouraging advances in treatment, particularly for metastatic pancreatic NETs and advanced low-grade tumors. Data presented at the ESMO 2024 Congress showed that three new antiangiogenic drugs may be effective against neuroendocrine tumors.

What Are Neuroendocrine Tumors? Types and Disease Course

Neuroendocrine tumors (NETs) are rare tumors arising from neuroendocrine cells, which have characteristics of both nerve cells and hormone-secreting cells. Their incidence is reported at approximately 5-6 new cases per 100,000 people. They most commonly arise in the gastrointestinal tract (particularly the small intestine, stomach, pancreas, and rectum) and lungs. Although more common at ages 50-60, they can occur at any age.

Neuroendocrine tumors range from low-grade, well-differentiated tumors to high-grade, rapidly growing neuroendocrine carcinomas. Their course varies with tumor type, spread, stage, and grade. Prognosis is better for NETs detected early, while survival is generally shorter in metastatic cases. Molecular and targeted therapies have nevertheless brought improvements in recent years.

RELATED TOPIC: Neuroendocrine Tumor Symptoms, Stages, and Treatment

A New Drug Candidate on the Scene: CVM-1118

In a phase IIa, single-arm study, the oral anti-vasculogenic mimicry agent CVM-1118 showed a better safety and tolerability profile than existing targeted therapies. Median progression-free survival (PFS) was 10.5 months in 43 patients with advanced NETs unresponsive to standard treatment. This exceeded the 4-6 months observed in placebo groups of existing treatments such as sunitinib and everolimus. In a subgroup receiving CVM-1118 with a somatostatin analogue, median PFS reached 22.4 months. Dr. Louis de Mestier described the results as encouraging but requiring further investigation.

Figure. In a phase IIa study of advanced NETs, CVM-1118 treatment resulted in significantly longer PFS than historical placebo data (ESMO 2024 Congress, Abstract 1145MO).

Ramucirumab Plus Dacarbazine: A Promising Option

The phase II RamuNET study evaluated ramucirumab plus dacarbazine in metastatic pancreatic NETs (grades 1-3). In 45 patients, the combination produced a 6-month disease control rate of 71.1%. Dr. de Mestier noted that combinations of this kind, like streptozotocin plus bevacizumab, offer promising strategies. However, without a control group, he added, it is difficult to say definitively whether the combination truly has a synergistic effect.

Cabozantinib and NETs with Low Proliferative Grade

The CABONEN study examined cabozantinib’s effectiveness and safety in patients with NETs of low proliferative grade. Median PFS was 6.7 months; however, the inclusion of some patients with neuroendocrine carcinoma and the fact that 71% had received prior treatment may explain the lower results. There were also 37 serious adverse events, 3 of which resulted in death. Dr. de Mestier emphasized that cabozantinib’s tolerability may be a concern.

Future Strategies for Antiangiogenic Agents

Discussing these study designs, Dr. de Mestier said that RECIST staging criteria used for antiangiogenic agents can sometimes be inadequate. He also emphasized the need for new biomarkers and plasma analyses to predict their effectiveness in NET treatment. Highlighting the need for both plasma and imaging biomarkers, he called for further strategy studies on which agents to use when resistance develops.

Conclusion

New antiangiogenic agents offer encouraging results for neuroendocrine tumors, particularly in advanced and metastatic disease. However, more research is needed to integrate them into clinical practice and improve their effectiveness.