Cabozantinib in well-differentiated metastatic pancreatic neuroendocrine tumors: a promising addition to the therapeutic arsenal
Syeda Samia Fatima1
, Hamdia Gul Aslam2
, Sarah Zaka2
, Syeda Faiqa Imran3
Received: 19 July 2025; Accepted: 08 August 2025; Published online: 28 August 2025.
doi: 10.21037/apc-25-13
Dear editor,
Pancreatic neuroendocrine tumors (pNETs), though often indolent, exhibit progressive malignant potential, with the majority of patients presenting at a metastatic stage (1). Despite the rising incidence, existing therapies—including somatostatin analogs (SSAs), everolimus, and sunitinib—offer modest improvements in progression-free survival (PFS) and often lack durable efficacy in advanced disease (2). The recent approval of cabozantinib in March 2025 by the U.S. Food and Drug Administration (FDA) for well-differentiated, metastatic pNETs marks a significant shift in the therapeutic landscape (3).
The standard of care for pNETs involves a combination of surgical, medical, and locoregional treatments (Table 1). Surgical resection remains the mainstay for localized disease. SSAs such as octreotide and lanreotide provide symptom control and may slow tumor progression. Targeted agents like sunitinib and everolimus are approved for advanced or progressive well-differentiated pNETs. Cytotoxic chemotherapy is generally reserved for poorly differentiated tumors or rapidly progressive disease, with combinations like temozolomide and capecitabine showing promising response rates. Locoregional therapies such as ablation and chemoembolization are also options for liver-dominant disease. Enrollment in clinical trials is encouraged, particularly for patients with advanced, unresectable tumors (4-6).
Table 1
| Treatment modality | Examples/agents | Key study | Limitations |
|---|---|---|---|
| Surgery | Surgical resection of primary/metastatic pNET | (4) | Although surgery improves survival even in metastatic pNETs, it remains non-feasible in cases of unresectable disease or extensive metastasis |
| Targeted therapy—everolimus | Everolimus (mTOR inhibitor) | (5) | Although everolimus significantly prolonged PFS, only 5% achieved a partial response, and disease progression eventually occurred in most patients despite therapy |
| Targeted therapy—sunitinib | Sunitinib (VEGF/PDGF TKI) | (5) | Sunitinib improved PFS and disease control, but ORR remained low (~9%), and resistance often developed over time |
| SSAs | Octreotide LAR, lanreotide | (6) | Most patients achieved disease stabilization, but no objective tumor regression was observed, confirming limited antiproliferative potential in progressive disease |
| CAPTEM | Capecitabine + temozolomide | (6) | CAPTEM demonstrated improved PFS and ORR, but was associated with grade 3–4 hematologic toxicity (e.g., neutropenia, thrombocytopenia), and further validation in larger cohorts is warranted |
CAPTEM, chemotherapy and temozolomide; LAR, long-acting release; mTOR, mechanistic target of rapamycin; ORR, objective response rate; PDGF, platelet-derived growth factor; PFS, progression-free survival; pNETs, pancreatic neuroendocrine tumors; SSAs, somatostatin analogs; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.
Cabozantinib exerts anti-tumor effects primarily through inhibition of angiogenesis, a key driver in NET progression. It blocks vascular endothelial growth factor (VEGF), mesenchymal-epithelial transition (MET), and AXL receptors—critical to tumor proliferation, angiogenesis, and invasiveness—thereby inhibiting abnormal blood vessel formation and promoting vascular normalization (7,8).
In a randomized cohort study of 95 patients with pNETs, cabozantinib demonstrated a median PFS of 13.8 vs. 4.4 months in the placebo group. Administered orally at 60 mg daily, cabozantinib delayed the need for subsequent anticancer therapies—required by only 45% of treated patients compared to 67% receiving placebo. Furthermore, it reduced the risk of disease progression or death by 62%. In those with pancreatic neuroendocrine tumors, the median PFS, which refers to the length of time during and after treatment that a patient lives without the disease worsening, was 13.8 months with cabozantinib vs. 4.4 months with placebo (8). These results support that cabozantinib, in comparison to placebo, has significantly improved PFS in patients with progressively advanced extrapancreatic or pNETs, which were previously treated as well.
However, one key limitation is the lack of predictive biomarkers, impeding precise patient selection and risking exposure to side effects without guaranteed benefit. Additionally, resistance may emerge through mechanisms such as c-MET upregulation, further complicating long-term management (6). Adverse effects—most notably hypertension, fatigue, and thromboembolic events—also require careful monitoring (8,9).
To optimize cabozantinib’s utility, future studies should compare its efficacy with other tyrosine kinase inhibitors (TKIs) while investigating resistance mechanisms and biomarker development. This will refine patient selection and dosing strategies, paving the way for more personalized therapy.
Combining cabozantinib with immune checkpoint inhibitors is another avenue worth exploring. Early-phase trials in renal and prostate cancers have demonstrated enhanced PFS with such combinations (10,11). Nonetheless, these findings are primarily derived from non-randomized studies, and larger randomized trials are essential to establish efficacy and safety across tumor types (12,13). For pNETs specifically, the potential for combination regimens represents an evolving frontier.
In conclusion, cabozantinib offers a meaningful advancement in the management of metastatic, well-differentiated pNETs. Despite its promise, challenges related to resistance, toxicity, and patient stratification remain. Future research should focus on biomarker discovery, resistance pathways, and combination strategies to fully harness its therapeutic potential.
Acknowledgments
None.
Footnote
Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.
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Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-25-13/coif). The authors have no conflicts of interest to declare.
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Cite this article as: Fatima SS, Aslam HG, Zaka S, Imran SF. Cabozantinib in well-differentiated metastatic pancreatic neuroendocrine tumors: a promising addition to the therapeutic arsenal. Ann Pancreat Cancer 2025;8:10.
