FDA Clears Cabozantinib as New Treatment Option for Advanced Neuroendocrine Tumors—First Systemic Therapy with Broad Applicability Across Disease Subtypes

Neuroendocrine tumors (NET) represent one of the most challenging cancer types to treat, with limited effective options for patients whose disease has progressed despite prior therapy. The U.S. Food and Drug Administration has now granted approval to cabozantinib, marking a significant shift in the treatment landscape for this heterogeneous disease.

The Clinical Challenge Behind the Approval

NET are rare cancers arising from specialized neuroendocrine cells, most commonly originating in the gastrointestinal tract, pancreas, or lungs. The disease presents a daunting prognosis—estimated at 380,000 cases in the U.S., with approximately 161,000 to 192,000 individuals living with advanced, metastatic forms. The five-year survival outlook varies dramatically depending on tumor location: only 23% for pancreatic cases compared to 55% for lung-derived tumors and 68% for GI tract cancers.

What makes NET especially difficult to manage is their biological heterogeneity. Tumors vary widely in grade, hormone secretion patterns, and somatostatin receptor expression—factors that historically limited treatment options to a narrow set of interventions. Most patients with advanced disease eventually face disease progression and develop resistance to standard approaches.

The CABINET Trial: Evidence-Based Breakthrough

The FDA approval rests on robust clinical evidence from the CABINET phase 3 trial, a multicenter, randomized, double-blind study sponsored by the National Cancer Institute and conducted through the Alliance for Clinical Trials in Oncology. The trial enrolled 298 patients across two disease cohorts—99 with pancreatic NET (pNET) and 199 with extra-pancreatic NET (epNET)—randomizing them 2:1 to receive either cabozantinib at 60mg daily or placebo.

The results demonstrated meaningful clinical benefit: cabozantinib significantly extended progression-free survival compared to placebo across both tumor types, regardless of primary tumor location, histological grade, or somatostatin receptor status. This broad efficacy across diverse disease presentations was unprecedented. Final progression-free survival data, presented at the 2024 European Society for Medical Oncology Congress and published in The New England Journal of Medicine, provided the evidence base for regulatory approval.

“What distinguishes this approval is that cabozantinib shows benefit independent of the tumor’s specific characteristics,” explained Jennifer Chan, M.D., M.P.H., clinical director of the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute and study chair for CABINET. “For a disease as heterogeneous as NET, that represents a meaningful advancement.”

Expanding the Treatment Arsenal

Cabozantinib is now the only systemic therapy approved by the FDA for previously treated NET without restrictions based on tumor site, grade, or molecular markers. This distinction matters enormously for patients and physicians—it eliminates the need for tumor-specific genetic or receptor testing to determine treatment eligibility.

The approval adds to five previous FDA clearances for cabozantinib, which is already established as a treatment for advanced renal cell carcinoma, hepatocellular carcinoma, and differentiated thyroid cancer. The January 2025 update to the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Neuroendocrine and Adrenal Tumors reflects this new role, listing cabozantinib as a category 1 preferred regimen for most well-differentiated advanced NET following prior therapies.

Managing Safety While Optimizing Benefit

The safety profile observed in the CABINET trial remained consistent with cabozantinib’s known tolerability pattern from other cancer indications. However, NET patients experienced a higher incidence of hypertension—a finding requiring close clinical monitoring. A majority of patients required dose modifications or reductions to manage treatment-related adverse events, underscoring the importance of individualized dose management.

Grade 3-5 hemorrhagic events occurred in approximately 5% of patients, while thrombotic events and gastrointestinal complications (fistulas and perforations) each affected roughly 1-2% of the population. No unexpected safety signals emerged from the trial data.

What This Means for the NET Community

For patients who have already received one or more lines of prior systemic therapy—whether somatostatin analogs, chemotherapy, or molecular targeted agents—cabozantinib offers a new pathway forward. The approval acknowledges both the unmet medical need and the clinical reality that NET progression eventually develops in all patients with advanced disease.

Cindy Lovelace, co-founder of The Healing NET Foundation and a long-term NET survivor, emphasized the practical significance: “With so few targeted therapies approved for advanced NET in recent years, this represents genuine hope for patients facing limited options after prior treatment.”

Looking ahead, the company plans to launch the STELLAR-311 pivotal trial in the first half of 2025, comparing cabozantinib with everolimus in NET—a study that could further refine treatment sequencing strategies for this patient population.