New data confirms cabozantinib significantly extends progression-free survival for patients with advanced neuroendocrine tumors (NETs), demonstrating consistent benefits regardless of whether the tumor is functional or non-functional. Targeted Oncology reported this important finding from the CABINET trial, a phase 3 study that supported the drug's FDA approval in March 2025. This news provides crucial clarity for clinicians treating a complex disease with varied clinical courses.
For years, functional tumors—which produce hormones that cause distinct symptoms like carcinoid syndrome—and non-functional tumors, which do not, have been considered separate entities with potentially different prognoses and treatment pathways. This has often led to clinical uncertainty, particularly for patients with functional tumors whose symptom burden already complicates their disease management. The CABINET analysis directly addresses this gap, reinforcing cabozantinib as a strong option for a broader patient population.
Cabozantinib Works for Both Functional and Non-Functional Advanced NETs
- Cabozantinib works for both hormone-secreting (functional) and non-secreting (non-functional) advanced NETs.
- The benefit is strong and clear: disease progression is delayed by 9.4 to 12.7 months, a significant improvement over placebo.
CABINET Trial Had Two Independent Cohorts
The CABINET (Alliance A021602) study was a randomized, double-blind, placebo-controlled phase 3 trial designed to provide definitive evidence for cabozantinib’s efficacy. It consisted of two independent cohorts: 203 patients with extra-pancreatic NETs (epNETs) and 95 patients with pancreatic NETs (pNETs). Within each cohort, participants were randomly assigned in a 2:1 ratio to receive either cabozantinib 60 mg daily or a placebo. A key design feature allowed patients on the placebo arm to “cross over” to receive open-label cabozantinib after their disease was confirmed to have progressed by central radiology review.
Eligible patients had well- to moderately differentiated grade 1 to 3 NETs with documented disease progression by RECIST criteria within 12 months before randomization. Crucially, all patients had previously progressed on, or were intolerant to, at least one other FDA-approved systemic therapy, such as everolimus or sunitinib, excluding somatostatin analogues (SSAs). Stable SSA therapy was permitted if the dose had been consistent for at least two months. For this specific functional status analysis, 45 patients with unknown hormone status were excluded to ensure clear subgroup comparisons.
Functional vs. Non-Functional Tumors: A Tale of Two Courses
The analysis revealed significant baseline differences between the functional and non-functional tumor groups, showing why this question was so clinically relevant. Functional tumors—those causing symptoms through hormone secretion—most commonly arose in the gastrointestinal (GI) tract. In contrast, non-functional tumors more frequently originated in the pancreas and lungs. This difference in origin also dictated the types of hormones produced; functional GI and lung NETs predominantly secreted serotonin, consistent with carcinoid syndrome, while functional pNETs produced a broader mix, including gastrin, glucagon, and insulin.
Concurrent SSA use was a major distinguishing factor. Roughly 90% of patients with functional tumors were receiving somatostatin analog therapy, compared to about half of those with non-functional tumors. This raised a key question: could the ongoing use of SSAs, which themselves have anti-tumor effects, dilute or confound the observed benefits of cabozantinib? The trial’s design, which required all enrolled patients to have progressive disease on prior therapies, helps to isolate the effect of the new drug.
Consistent Efficacy Across Subgroups
The results from the subgroup analysis were striking for their consistency. The progression-free survival (PFS) benefit was numerically greater in the functional group, with a median PFS of 12.7 months compared to 9.4 months in the non-functional group. Both figures represent a substantial improvement over placebo, with PFS in the functional group being more than double that of the control, and in the non-functional group, approximately three times better.
Safety and Symptom Burden Considerations
A primary concern in treating functional NETs is the potential for overlapping toxicities between cabozantinib and existing symptom management. Dr. Trikalinos noted that these patients “have different trajectories, different treatments” and that a key concern was whether the side effects of cabozantinib might add to the symptom burden patients with functional tumors already carry. However, the safety data showed no significant difference in the side effect profiles between the functional and non-functional groups. Particularly with common adverse events like diarrhea and hypertension, the rates were comparable, providing reassurance to clinicians.
| Cabozantinib Efficacy in Advanced NETs by Functional Status | Median Progression-Free Survival (PFS) |
|---|---|
| Functional Tumors | 12.7 months |
| Non-Functional Tumors | 9.4 months |
Bridging the Gap: Regulatory and Global Access
The positive results from the CABINET trial led to a significant regulatory milestone. In March 2025, the U.S. Food and Drug Administration (FDA) granted approval for cabozantinib to treat adult and pediatric patients 12 years and older with previously treated, well-differentiated pNETs and epNETs. This approval was based on the primary analysis showing a statistically significant improvement in PFS. The new subgroup analysis, presented in November 2026, further solidifies the drug's position in the treatment field by confirming its applicability across the functional/non-functional divide.
Consult Oncologist Before Starting Cabozantinib
Cabozantinib is a powerful targeted therapy with a specific set of contraindications. Anyone considering this therapy should consult with their oncologist to discuss their complete medical history.
Looking Ahead and Unanswered Questions
Despite the clarity provided by this analysis, several important questions remain. A key area of ongoing investigation is whether cabozantinib has a direct effect on hormone secretion and symptom control in functional tumors. While the drug effectively controls tumor growth, its ability to mitigate symptoms like flushing or diarrhea caused by hormone overproduction is not yet established. Analyses of biochemical response, including changes in tumor markers such as 5-hydroxyindoleacetic acid (5-HIAA), are ongoing but are limited by the small number of patients in some hormone-specific subgroups.
The full publication of the CABINET trial data is anticipated to provide more detailed biomarker analyses that could further refine treatment selection for specific patient subgroups.
References
- Trikalinos NA, Geyer S, Zemla T, et al. Presented at: 2026 NANETS Multidisciplinary NET Medical Symposium; November 5-7, 2026; Las Vegas, NV.
- Chan JA, Geyer S, Zemla T, et al. Phase 3 trial of cabozantinib to treat advanced neuroendocrine tumors. N Engl J Med. 2025;392(7):653-665. doi:10.1056/NEJMoa24039913.
- US Food and Drug Administration. March 26, 2025. Accessed November 6, 2026.
