Cabozantinib Found Effective in Treating Advanced Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are rare but complex tumors usually found in the gastrointestinal tract, lungs and pancreas. Treatment of advanced NETs is planned according to tumor location, hormone-secreting capacity, disease extent and pathological classification. Existing options include somatostatin analogues, peptide receptor radionuclide therapy (PRRT), targeted therapies such as everolimus and sunitinib, and chemotherapy. In advanced disease, however, particularly after multiple previous treatments, these therapies fail to remain effective over the long term in many patients, making disease progression inevitable.

Cabozantinib is a molecule that inhibits multiple tyrosine kinase receptors (VEGF, MET, AXL and RET). In neuroendocrine tumors, angiogenesis (the formation of new blood vessels) plays a critical role in tumor growth and spread. Cabozantinib aims to block these processes by targeting VEGF pathways.

Published on September 16, 2024, in NEJM, this phase 3 clinical trial evaluated the effectiveness of cabozantinib in slowing disease progression in patients with advanced neuroendocrine tumors.

The CABINET Trial

The CANINET trial included two independent groups of patients whose disease had progressed after previous peptide receptor radionuclide therapy (PRRT) or targeted therapy (everolimus or sunitinib):

• The Extrapancreatic Neuroendocrine Tumor Group
• The Pancreatic Neuroendocrine Tumor Group

Patients were randomly assigned in a 2:1 ratio to receive cabozantinib (60 mg daily) or placebo. Cabozantinib's efficacy was measured by progression-free survival, which assesses the time until disease progression. Secondary endpoints, including objective response rate, overall survival and safety profile, were also examined.

Study Data and Results

Extrapancreatic Neuroendocrine Tumor Group:

In this group of 203 patients, cabozantinib significantly slowed disease progression compared with placebo.

• Progression-Free Survival:

  • Cabozantinib Group: 8.4 months
  • Placebo Group: 3.9 months
  • Risk Reduction: 62% (HR: 0.38, 95% CI: 0.25-0.59, P<0.001)

• Objective Response Rate (Patients With a Reduction in Tumor Size):

  • Cabozantinib Group: 5% (95% CI: 2-10)
  • Placebo Group: 0% (95% CI: 0-5)

Pancreatic Neuroendocrine Tumor Group:

In this group of 95 patients, cabozantinib slowed the progression of pancreatic neuroendocrine tumors more than placebo.

• Progression-Free Survival:

  • Cabozantinib Group: 13.8 months
  • Placebo Group: 4.4 months
  • Risk Reduction: 77% (HR: 0.23, 95% CI: 0.12-0.42, P<0.001)

• Objective Response Rate:

  • Cabozantinib Group: 19% (95% CI: 10-30)
  • Placebo Group: 0% (95% CI: 0-11)

Side Effects and Safety Profile

In both patient groups, cabozantinib's safety profile was as expected, with more side effects than placebo. In the extrapancreatic neuroendocrine tumor group, 62% of patients receiving cabozantinib experienced serious side effects (grade 3 or higher), compared with 27% in the placebo group. In the pancreatic neuroendocrine tumor group, serious side effects were reported in 65% of patients receiving cabozantinib, compared with 23% in the placebo group.

The most common serious side effects were:

• Hypertension: 21-22%
• Fatigue: 11-13%
• Diarrhea: 11% (extrapancreatic)
• Thromboembolic Events: 11% (pancreatic)

Side effects could generally be managed by reducing the cabozantinib dose. Dose reductions were made in 66% of patients receiving cabozantinib.

Discussion: The Future of Cabozantinib

This study showed that cabozantinib significantly slowed disease progression in both extrapancreatic and pancreatic neuroendocrine tumors. It may be an important treatment option for patients who have not responded to previous therapies or whose disease has progressed after treatment. In both groups, cabozantinib significantly prolonged the time to disease progression and produced higher tumor response rates than placebo. However, overall survival data were immature, and early termination of the study prevented these outcomes from being clarified.

Advantages of Cabozantinib:

1. Slowing disease progression by 62% in extrapancreatic neuroendocrine tumors.
2. Slowing disease progression by 77% in pancreatic neuroendocrine tumors.
3. High objective response rates: 5% in extrapancreatic NETs and 19% in pancreatic NETs.
4. Side effects were manageable, and dose reduction provided an effective solution for most patients.

Side Effects and Challenges:

1. Higher rates of serious side effects (grade 3 or higher), particularly hypertension, fatigue and diarrhea.
2. A substantial proportion of patients required dose reductions.

Conclusion: Cabozantinib's Place in Treatment Sequencing

The results suggest that cabozantinib could gain an important place in the treatment of neuroendocrine tumors. Future clinical trials should examine its combinations with existing treatments and its place in treatment sequencing in greater depth. Cabozantinib's efficacy and safety, particularly after PRRT and targeted therapies, may make it an important alternative in clinical practice.