What are the treatment options for a pancreatic grade 2 neuroendocrine tumor (NET) with liver metastases after resection of the primary tumor, involving CTLA4 (Cytotoxic T-Lymphocyte Antigen 4), PD-L1 (Programmed Death-Ligand 1), and considering RBS2418?

From the Guidelines

Treatment for a pancreatic grade 2 neuroendocrine tumor with liver metastases after primary tumor resection should prioritize somatostatin analogs, such as octreotide LAR or lanreotide, to control hormone-related symptoms and potentially slow tumor growth, as supported by the most recent evidence from 2025 1. The management of pancreatic neuroendocrine tumors (pan-NETs) is complex and depends on various biological and clinical characteristics.

• First-line treatment typically includes somatostatin analogs such as octreotide LAR (20-30 mg intramuscularly every 4 weeks) or lanreotide (120 mg subcutaneously every 4 weeks) to control hormone-related symptoms and potentially slow tumor growth.
• For progressive disease, targeted therapies like everolimus (10 mg orally daily) or sunitinib (37.5 mg orally daily) have shown efficacy, as demonstrated in previous studies 1.
• Given the involvement of immune checkpoint markers CTLA4 and PD-L1, immunotherapy combinations may be considered, such as ipilimumab (1 mg/kg IV) plus nivolumab (3 mg/kg IV) every 3 weeks for 4 doses, followed by nivolumab maintenance (240 mg IV every 2 weeks).
• Peptide receptor radionuclide therapy (PRRT) with lutetium-177 dotatate (200 mCi IV every 8 weeks for 4 cycles) is another effective option if the tumor shows high somatostatin receptor expression on imaging.
• For liver-dominant disease, liver-directed therapies including transarterial chemoembolization, radioembolization, or ablation may provide localized control.
• While RBS2418 appears to be an investigational agent, clinical trials exploring novel therapies should be considered, as suggested by recent reviews 1. Treatment selection should be guided by tumor characteristics, disease burden, progression rate, and patient performance status, with a multidisciplinary tumor board approach recommended for optimal sequencing of these therapies. The use of streptozotocin in managing pancreatic neuroendocrine neoplasms has been systematically reviewed, providing evidence for its efficacy in certain cases 1. However, the most recent and highest-quality study should always be prioritized when making treatment decisions, ensuring the best possible outcomes in terms of morbidity, mortality, and quality of life.

From the FDA Drug Label

1.4 Advanced Pancreatic Neuroendocrine Tumors Sunitinib malate capsules are indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease.

The treatment options for a pancreatic grade 2 neuroendocrine tumor (NET) with liver metastases after resection of the primary tumor may include sunitinib.

• Key points:
  • Sunitinib is indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease.
  • The recommended dosage of sunitinib malate capsules for pancreatic neuroendocrine tumors (pNET) is 37.5 mg taken orally once daily until disease progression or unacceptable toxicity.
  • CTLA4, PD-L1, and RBS2418 are not mentioned in the provided drug labels as being directly related to the treatment of pancreatic NETs with sunitinib or lanreotide.
  • Lanreotide is indicated for the treatment of adult patients with unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival, but the provided context does not specify its use for pancreatic grade 2 NET with liver metastases after resection of the primary tumor. 2 2

From the Research

Treatment Options for Pancreatic Grade 2 NET with Liver Metastases

• The treatment of pancreatic neuroendocrine tumors (pNETs) depends on pathological grading, clinical staging, and presence of symptoms related to hormonal secretion 3.
• For advanced pNETs, everolimus and sunitinib have been shown to significantly improve progression-free survival 4.
• Somatostatin analogs, such as octreotide and lanreotide, are recommended for treating endocrine symptoms of functional pNETs, but their antitumor effect is still being studied 5.
• In cases of unresectable pNETs, a debulking operation or liver-directed therapies may be effective in controlling the disease 4.

Role of CTLA4, PD-L1, and RBS2418 in Treatment

• There is limited information available on the specific role of CTLA4, PD-L1, and RBS2418 in the treatment of pancreatic grade 2 NET with liver metastases.
• However, studies have shown that immunotherapy targeting CTLA4 and PD-L1 can be effective in treating various types of cancer, including neuroendocrine tumors 3, 4.
• Further research is needed to determine the potential benefits and risks of using these therapies in combination with other treatments, such as somatostatin analogs and liver-directed therapies.

Prognosis and Survival

• The prognosis and survival of patients with pancreatic grade 2 NET with liver metastases depend on various factors, including tumor grade, hepatic tumor load, and treatment response 6.
• A study found that patients with grade 2 tumors and hepatic tumor load ≤25% appeared to derive higher benefit from somatostatin analogs, with a median progression-free survival of 11.9 months and median overall survival of 86 months 6.
• However, more research is needed to determine the optimal treatment strategies for this specific patient population and to improve outcomes.