What are the most suitable trials for a pancreatic neuroendocrine tumor (PNET) that has metastasized to the liver?

From the Guidelines

For metastatic pancreatic neuroendocrine tumors (NETs) that have spread to the liver, long-acting somatostatin analogs, bland transarterial embolization (TAE), peptide receptor radionuclide therapy (PRRT), transarterial chemoembolization (TACE), or transarterial radioembolization (TARE) are usually appropriate management options. These procedures are comparable alternatives and can be used to effectively manage the patient's care 1.

When considering treatment options, it's essential to evaluate the tumor's characteristics, such as grade, proliferation index (Ki-67), and somatostatin receptor status, as well as the patient's previous treatments. For example:

• Well-differentiated, low to intermediate-grade NETs with positive somatostatin receptor imaging may benefit from trials investigating somatostatin analogs like octreotide LAR (30 mg every 4 weeks) or lanreotide (120 mg every 4 weeks) in combination with newer agents.
• Patients with specific genetic mutations may be eligible for trials targeting the mTOR pathway with everolimus (10 mg daily) or trials using tyrosine kinase inhibitors like sunitinib (37.5 mg daily).
• PRRT trials using Lutetium-177 dotatate, especially in combination with other treatments, are also highly relevant for patients with metastatic pancreatic NETs.

Comprehensive molecular profiling of the tumor can help identify potential actionable mutations, making patients eligible for specific targeted therapy trials 1.

In terms of clinical trials, those focusing on targeted therapies, immunotherapies, or novel combinations are most suitable for metastatic pancreatic NETs that have spread to the liver. The choice of trial should be guided by the tumor's characteristics and the patient's previous treatments, with the goal of improving morbidity, mortality, and quality of life outcomes.

From the FDA Drug Label

The major efficacy outcome measure was progression-free survival (PFS), defined as time to disease progression as assessed by central independent radiological review using the Response Evaluation Criteria in Solid Tumors (RECIST 1.0) or death.

Patients in the lanreotide arm had a statistically significant improvement in PFS compared to patients receiving placebo.

A clinically significant improvement for sunitinib over placebo in PFS was seen by both investigator and independent assessment.

The most suitable trial for a pancreatic net that metastasized to the liver is Study 6 for sunitinib or Study 3 for lanreotide, as both studies showed a statistically significant improvement in Progression-Free Survival (PFS) in patients with pancreatic neuroendocrine tumors (pNET) or gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with liver metastases 2 3.

• Key points:
  • Sunitinib:
    • PFS: 10.2 months (95% CI: 7.4,16.9) vs 5.4 months (95% CI: 3.4,6.0) for placebo.
    • Hazard Ratio (HR): 0.427 (95% CI: 0.271,0.673).
  • Lanreotide:
    • PFS: Not Estimated (NE) vs 16.6 months (95% CI: 11.2,22.1) for placebo.
    • HR: 0.47 (95% CI: 0.30,0.73).

From the Research

Treatment Options for Pancreatic Neuroendocrine Tumors with Liver Metastases

• Surgery is the only curative treatment for localized pancreatic neuroendocrine tumors (pNETs) and an aggressive surgical approach towards liver metastases is recommended in selected cases 4
• Liver-directed therapies, such as liver transplantation, may be considered for disease control in patients with unresectable liver metastases 5
• Systemic therapies, including somatostatin analogs, targeted therapies (e.g. everolimus), peptide receptor radionuclide therapy, and systemic chemotherapy, are useful tools for prolonging survival in patients with unresectable progressive disease 4, 6
• Somatostatin analogs may exert antiproliferative activity in pNETs with Ki-67 ≥10%, particularly in grade 2 tumors and when hepatic tumor load is ≤25% 7

Considerations for Treatment Selection

• The biologic behavior of pNETs is defined by the grade and stage of the tumor, and treatment selection should take into account these factors 4
• The presence of liver metastases and the extent of hepatic tumor load are important considerations in treatment selection 7, 5
• Molecular mechanisms and therapeutic targets, such as the mTOR and receptor tyrosine kinase (RTK) pathways, may guide the use of targeted therapies in patients with advanced disease 8