Cabozantinib has shown a significant improvement in progression-free survival (PFS) compared to placebo in patients with advanced pancreatic neuroendocrine tumors (pNET) and advanced extra-pancreatic neuroendocrine tumors (epNET). The findings, from the Phase III CABINET trial (NCT03375320), were presented at the 2024 European Society for Medical Oncology Congress and published in The New England Journal of Medicine. The study suggests that cabozantinib could become a new standard of care for this patient population.
CABINET Trial Details and Results
The multicenter, randomized, double-blinded, placebo-controlled CABINET trial enrolled 298 patients who were randomly assigned in a 2:1 ratio to receive cabozantinib at a dose of 60 mg or placebo. The trial included two separate cohorts: pNET (n=95) and epNET (n=203). The epNET cohort included patients with tumors of the gastrointestinal tract, lung, unknown primary sites, and other locations. Each cohort was analyzed separately.
In the pNET patient group (n=95), with a median follow-up of 13.8 months, median PFS was 13.8 months for cabozantinib versus 4.4 months in the placebo cohort (hazard ratio [HR] 0.23 [95% confidence interval [CI]: 0.12-0.42; p<0.0001]). Among patients with epNET (n=203), at a median follow-up of 10.2 months, median PFS was 8.4 months in the cabozantinib cohort compared to 3.9 months in the placebo cohort (HR 0.38 [95% CI: 0.25-0.59; p<0.0001]).
After disease progression, patients were unblinded, and the placebo cohort was allowed to cross over to open-label therapy with cabozantinib. In the pNET cohort, the objective response rate (ORR) as per blinded independent central review (BICR) was 19% in the cabozantinib cohort vs. 0% in the placebo cohort. Among patients in the epNET cohort, ORR per BICR was 5% in the cabozantinib cohort vs. 0% in the placebo cohort.
Safety Profile
Grade 3 or higher adverse events (AEs) were reported in 62% to 65% of patients administered cabozantinib compared to 23% to 27% of patients in the placebo cohort. The most frequently reported treatment-related AEs of grade 3 or higher included hypertension, fatigue, diarrhea, and thromboembolic events. These adverse events were generally managed with dose reductions.
Regulatory and Clinical Implications
Based on these findings, the FDA accepted a supplemental new drug application (sNDA) for cabozantinib for the treatment of previously treated, locally advanced/unresectable or metastatic, well- or moderately differentiated pNETs and epNETs in August. Cabozantinib was also granted Orphan Drug Designation for the pNET indication. The FDA assigned the sNDA a Prescription Drug User Fee Act target action date of April 3, 2025.
According to Dr. 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, the CABINET study reflects real-world clinical practice by enrolling a wide range of patients regardless of primary tumor site, grade, somatostatin receptor expression, and functional status. She expressed encouragement that the final results showed cabozantinib provided a clinically meaningful treatment benefit for patients with previously treated advanced neuroendocrine tumors, including across all major clinical subgroups.
Cabozantinib, an oral small molecule tyrosine kinase inhibitor, is currently approved as monotherapy for advanced renal cell carcinoma (RCC) and in combination with nivolumab as first-line treatment for advanced RCC; for patients with hepatocellular carcinoma previously treated with sorafenib, and for patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer that progressed after previous VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible.
