Cabozantinib: a promising advancement in the treatment of advanced neuroendocrine tumors

Gastroenteropancreatic neuroendocrine tumors (GEP NETs) pose a significant treatment challenge due to their diverse biological behaviors and limited therapeutic options. The complexity of managing advanced GEP NETs is increased by the difficulty in establishing an optimal therapeutic sequence, as treatment decisions must consider tumor grade, differentiation, and somatostatin receptor (SSTR) expression while balancing efficacy with tolerability (1-3). The complexity increases in real-world settings due to individual patient variations and differing disease progression rates, complicating the effective implementation of standardized treatment approaches. Radioligand therapy (RLT) is recognized as an effective and safe second-line treatment after somatostatin analogs (SSA) for SSTR-positive tumors. RLT indications are expected to be soon expanded into high-grade tumors and used as a retreatment option (4). Multi-targeted agents in GEP NETs represent an effective approach due to their ability to inhibit multiple pathways involved in tumor growth and angiogenesis, which are implicated in the proliferation and survival of NET cells.

Cabozantinib (CBZ) is an oral tyrosine kinase inhibitor targeting several kinases, including vascular endothelial growth factor receptor 2 (VEGFR2), Axl receptor tyrosine kinase (AXL), Met proto-oncogene (MET), and rearranged during transfection (RET), crucial for tumor survival and metastasis. By concurrently inhibiting VEGFR and MET pathways, CBZ enhances disease control by preventing tumor spread that could occur through hypoxia-induced MET signaling activation (5).

Beyond GEP-NETs, CBZ has proven effective in other oncological settings. The Natalie trial assessed the activity and safety of CBZ in patients with metastatic phaeochromocytomas and paragangliomas. The trial found that CBZ showed promising activity, with a 25% overall response rate, and reported several grade 3 adverse events but no grade 4 events or deaths during the study. Adverse events included hypertension, fatigue, hand-and-foot syndrome, and hypothyroidism. Seven grade 3 toxicities were reported in six patients, including hypertension, QT prolongation, rectal fistula, and elevated pancreatic enzymes. While no grade 4 toxicities or treatment-related deaths occurred, 88% of patients required dose reductions to manage side effects (6).

The phase 3 trial of CBZ recently published in the New England Journal of Medicine (7) for treating advanced NETs addresses a significant gap in treatment options for patients with progressive extrapancreatic or pancreatic NETs who have already undergone other therapies. The trial, known as CABINET, was conducted to evaluate the efficacy and safety of CBZ compared to a placebo. The study enrolled patients with histologically confirmed, progressive NETs, randomly assigning them to either CBZ or a placebo. The primary endpoint was progression-free survival (PFS), with secondary endpoints including objective response rate, overall survival, and safety.

The trial’s results were promising. In the cohort with extrapancreatic NETs, CBZ significantly improved median PFS to 8.4 months compared to 3.9 months for placebo recipients. Similarly, in the pancreatic NET cohort, the median PFS was 13.8 months with CBZ vs. 4.4 months with placebo (Table 1). These findings indicate that CBZ effectively delays disease progression in both types of NETs.

Objective response rates also favored CBZ, with 5% of patients in the extrapancreatic cohort and 19% in the pancreatic cohort achieving a confirmed response, compared to none in the placebo groups. However, overall survival data were not mature at the time of analysis, showing no significant difference between the CBZ and placebo groups.

Safety is a critical consideration for any cancer therapy. In the CABINET trial (7), CBZ was associated with a higher incidence of grade 3 or higher adverse events compared to placebo—62–65% vs. 23–27%, respectively. Common adverse events included hypertension, fatigue, diarrhea, and thromboembolic events. Despite these side effects, the safety profile was consistent with previous studies of CBZ in other cancers.

The trial’s design allowed for dose adjustments to manage adverse events effectively. Most patients required dose reductions or interruptions due to side effects, highlighting the importance of balancing efficacy with tolerability. Based on the safety data from the Natalie trial (6), it is possible to hypothesize improved management of the adverse effect of arterial hypertension in patients receiving CBZ through close monitoring of blood pressure values and, in selected cases, the early initiation of antihypertensive therapy. This approach could enhance the tolerability of the drug with regard to arterial hypertension as a side effect.

The CABINET trial (7) underscores CBZ’s potential as a new treatment option for advanced NETs that have progressed after other therapies. Its ability to target multiple pathways involved in tumor growth and angiogenesis makes it particularly suited for these highly vascularized tumors.

Despite its promise, there are limitations to consider. The early termination of the trial based on interim analyses could lead to an overestimation of treatment effects. Additionally, using a placebo rather than an active comparator might limit the interpretation of results concerning existing therapies.

Other studies investigating the efficacy and safety of CBZ in GEP-NETS are ongoing. The LOLA trial (8) is a phase II study designed to evaluate the safety and effectiveness of CBZ combined with lanreotide in treating well-differentiated GEP and thoracic neuroendocrine tumors. This multicenter, open-label trial targets patients with advanced or metastatic, progressive, non-functioning NETs, focusing on those with a Ki67 index of 10% or higher. The study aims to determine the optimal dose of CBZ and assess its overall response rate and safety when combined with lanreotide. Secondary objectives include PFS and overall survival, with exploratory goals to identify potential biomarkers for treatment response.

Future research should focus on optimizing treatment sequencing and exploring combination therapies that might enhance CBZ’s efficacy while minimizing adverse effects. The role of resistance mechanisms also warrants further investigation to improve long-term outcomes for patients with advanced NETs.

CBZ represents a significant advancement in treating advanced NETs by improving PFS compared to placebo. Its efficacy in targeting key pathways involved in tumor progression offers a valuable option for patients who have exhausted other treatments. However, its safety profile requires careful management due to common severe adverse events. Integrating CBZ into treatment protocols could significantly alter management strategies for NETs, providing an additional option for personalized treatment plans based on individual patient needs and tumor characteristics.

Future research should focus on overall survival benefits and long-term safety to better understand CBZ’s full impact on patient health. Investigating CBZ in combination with other agents could enhance therapeutic efficacy and potentially reduce adverse effects by allowing lower dosages. Identifying biomarkers predictive of response to CBZ could personalize treatment strategies, ensuring that patients most likely to benefit from the drug receive it.

As we move forward, it is crucial to build upon these findings to unlock further potential benefits for patients with neuroendocrine tumors. Continued research will be essential to refine its use and explore potential synergies with other therapeutic agents.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-221/coif). The authors have no conflicts of interest to declare.

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