Cabozantinib Shows Significant PFS Improvement in Advanced Neuroendocrine Tumors
Key Insights
Cabozantinib significantly improved progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumors (search) (pNET) and extra-pancreatic NET (search) (epNET) compared to placebo.
In the pNET cohort, median PFS was 13.8 months for cabozantinib versus 4.4 months for placebo (HR 0.23, p<0.0001), while in the epNET cohort, median PFS was 8.4 months versus 3.9 months (HR 0.38, p<0.0001).
The objective response rate (ORR) was higher with cabozantinib in both cohorts, with 19% in pNET and 5% in epNET, suggesting potential clinical benefit across various subgroups.
Final results from the Phase III CABINET trial, presented at ESMO 2024 and published in the New England Journal of Medicine, demonstrate that cabozantinib provides a significant improvement in progression-free survival (PFS) for patients with previously treated advanced neuroendocrine tumors (search) (NETs). The study, which included cohorts with advanced pancreatic NETs (pNET) and extra-pancreatic NETs (epNET), met its primary objective in both groups.
Significant PFS Improvement
The CABINET trial (A021602) revealed compelling improvements in PFS based on blinded independent central review (BICR). In the pNET cohort, with a median follow-up of 13.8 months, median PFS was 13.8 months for cabozantinib compared to 4.4 months for placebo (HR 0.23 [95% CI: 0.12-0.42] p<0.0001). The epNET cohort, with a median follow-up of 10.2 months, showed a median PFS of 8.4 months versus 3.9 months for placebo (HR 0.38 [95% CI: 0.25-0.59] p<0.0001).
Objective Response and Subgroup Analysis
Additional analyses indicated benefits with cabozantinib across all clinical subgroups examined, including primary tumor site, grade, and prior systemic anticancer therapy. In the pNET cohort, the objective response rate (ORR) was 19% with cabozantinib compared to 0% with placebo. The epNET cohort showed an ORR by BICR of 5% with cabozantinib compared to 0% with placebo. Interim overall survival results were similar for cabozantinib compared to placebo in both cohorts, with HRs of 0.95 (95% CI: 0.45-2.00) for pNET and 0.86 (95% CI: 0.56-1.31) for epNET.
Safety Profile and Regulatory Implications
The safety profile of cabozantinib in each cohort was consistent with previous studies, with common side effects including hypertension, fatigue, and diarrhea. No new safety signals were identified.
These results have led to a supplemental new drug application (sNDA) for cabozantinib for the treatment of adults with advanced NETs, submitted by Exelixis. The FDA accepted the sNDA in August, assigning a Prescription Drug User Fee Act target action date of April 3, 2025.
Study Design
CABINET is a multicenter, randomized, double-blinded, placebo-controlled Phase III trial that enrolled 298 patients in two separate cohorts (pNET, n=95; epNET, n=203) in the United States. Patients were randomized 2:1 to cabozantinib or placebo. The primary endpoint was PFS in each cohort. Upon disease progression, patients on placebo could cross over to open-label cabozantinib. Secondary endpoints included overall survival, radiographic response rate, and safety.
Expert Commentary
"Given that there is no standard treatment for patients with progressive disease, these results showing notable improvements in progression-free survival are highly encouraging for patients and their physicians," said Dr. Jennifer Chan, Clinical Director of the Gastrointestinal Cancer Center and Director of the Program in Carcinoid and Neuroendocrine Tumors (search) at Dana-Farber Cancer Institute. "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."