FDA Approves Cabozantinib for Advanced Pancreatic Neuroendocrine Tumors

Cabozantinib (Cabometyx; Exelixis) received FDA approval after demonstrating a significant delay in disease progression in patients with pancreatic neuroendocrine tumors (pNET) and patients with extra-pancreatic neuroendocrine tumors (epNET).¹ The drug is indicated to treat pNET and epNET in adult and pediatric patients 12 years or older with previously treated, unresectable, locally advanced or metastatic, well-differentiated tumors.

Findings from the phase 3 CABINET trial (NCT03375320) supported the agency’s decision. The trial evaluated the efficacy of cabozantinib vs placebo in 2 separately powered cohorts: patients with advanced pNET (n = 99) and advanced epNET (n = 199). A significant delay in disease progression in both pNET and epNET cohorts was observed, regardless of primary tumor site or grade.

The multicenter, randomized, double-blind, placebo-controlled study enrolled 298 patients in the US. Participants were randomized 2:1 to receive cabozantinib (60 mg) or placebo, with progression-free survival (PFS) as the primary end point assessed by blinded independent central review using RECIST 1.1 criteria.

Results from the pNET cohort showed the intervention group (n = 66) achieved a median PFS of 13.8 months (95% CI, 8.9-17.0) compared with 3.3 months (95% CI, 2.8-5.7) in the placebo group (n = 33; HR, 0.22; 95% CI, 0.12-0.41; P < .0001).² Additionally, the overall response rate (ORR) with cabozantinib was 18% (95% CI, 10%-30%), while the placebo ORR was 0% (95% CI, 0%-11%). The median duration of response (DOR) was 11.4 months for those receiving cabozantinib, while it was not evaluable (NE) in the placebo group. Overall survival (OS) data were not mature (HR, 1.01).

In the epNET cohort, cabozantinib (n = 132) achieved a median PFS of 8.5 months (95% CI, 6.8-12.5) compared with 4.2 months (95% CI, 3.0-5.7) in the placebo group (n = 67; HR, 0.40; 95% CI, 0.26-0.61; P < .0001). The ORRs were 5% (95% CI, 2.2%-11%) for cabozantinib vs 0% (95% CI, 0%-5%) for placebo. A median DOR of 8.3 months was observed with cabozantinib (placebo DOR, NE). OS data in this cohort were not yet mature (HR, 1.01).

The safety data were consistent with the known profile of cabozantinib.¹ However, hypertension was more common in patients with NET compared with other approved indications, necessitating dose modifications for many participants.

In response to these findings, the National Comprehensive Cancer Network (NCCN) updated its 2025 Clinical Practice Guidelines in Oncology for Neuroendocrine and Adrenal Tumors, listing cabozantinib as:

• Category 1 preferred regimen for most well-differentiated advanced NET after specific prior treatments
• Category 2A preferred regimen for other forms of advanced NET, depending on tumor grade and prior therapy

The final CABINET trial results were presented at the 2024 European Society for Medical Oncology (ESMO) Congress and published in The New England Journal of Medicine.

“The findings suggest that cabozantinib has the potential to become a new standard of care for these patients greatly in need of new treatment options,” CABINET study chair Jennifer Chan, MD, MPH, clinical director of the Gastrointestinal Cancer Center and Director of the Program in Carcinoid and Neuroendocrine Tumors at Dana-Farber Cancer Institute, said in a statement in September.³

NET are rare but increasingly diagnosed tumors that originate from neuroendocrine cells of the digestive tract, pancreas, lungs, and other organs.¹ The prognosis for advanced NET varies, but many patients eventually develop refractory disease requiring additional treatment options.

"The characteristics of NET vary widely from patient to patient, and very few treatment options have demonstrated the ability to improve outcomes across such a heterogeneous population,” Chan stated in the news release announcing the approval. “It was encouraging to see that cabozantinib resulted in significant delays in disease progression in the CABINET trial—regardless of primary tumor site and grade. This FDA approval marks a meaningful advancement, which may establish an important new treatment option for patients, without limitations based on somatostatin receptor expression and functional status."

With strong PFS benefits demonstrated in the CABINET trial and updates to NCCN guidelines, this approval reinforces cabozantinib’s role in improving outcomes for patients facing these challenging cancers, according to Exelixis. In the announcement, the company committed to advancing NET treatment through its plans for the STELLAR-311 pivotal trial in 2025, which will compare zanzalintinib (XL092) vs everolimus (Afinitor).

References

1. Exelixis announces U.S. FDA approval of Cabometyx (cabozantinib) for patients with previously treated advanced neuroendocrine tumors. News release. Exelixis. March 26, 2025. Accessed March 26, 2025. https://ir.exelixis.com/news-releases/news-release-details/exelixis-announces-us-fda-approval-cabometyxr-cabozantinib-4

2. Rosa K. FDA approves cabozantinib for pancreatic and extra-pancreatic neuroendocrine tumors. OncLive. March 26, 2025. Accessed March 26, 2025. https://www.onclive.com/view/fda-approves-cabozantinib-for-pancreatic-and-extra-pancreatic-neuroendocrine-tumors

3. Exelixis announces final results from phase 3 pivotal CABINET study evaluating cabozantinib in advanced neuroendocrine tumors presented at ESMO 2024 and published in New England Journal of Medicine. News release. Exelixis. September 16, 2024. Accessed March 26, 2025. https://ir.exelixis.com/news-releases/news-release-details/exelixis-announces-final-results-phase-3-pivotal-cabinet-study