RCT: Cabozantinib Improves Progression-Free Survival in Advanced Neuroendocrine Tumors
17 Sep, 2024 | 11:03h | UTCBackground: Advanced neuroendocrine tumors (NETs) present limited treatment options, with many patients experiencing disease progression despite existing therapies. Angiogenesis is pivotal in NET pathogenesis. Cabozantinib, an oral tyrosine kinase inhibitor targeting VEGF receptors, MET, AXL, and RET, has demonstrated clinical activity in phase 2 studies involving NETs. The efficacy of cabozantinib in patients with progressive, advanced extrapancreatic or pancreatic NETs after prior treatments remains uncertain.
Objective: To assess the efficacy and safety of cabozantinib compared with placebo in patients with previously treated, progressive advanced extrapancreatic or pancreatic NETs.
Methods: A multicenter, double-blind, randomized, placebo-controlled phase 3 trial (CABINET) was conducted at 62 sites in the United States from October 2018 to August 2023. Eligible patients were adults aged ≥18 years with histologically confirmed, locally advanced or metastatic well- or moderately differentiated extrapancreatic or pancreatic NETs (WHO grades 1–3) and documented disease progression within 12 months prior to enrollment. Patients were randomized 2:1 to receive cabozantinib (60 mg orally once daily) or placebo. Randomization was stratified by concurrent somatostatin analogue use and primary tumor site. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review according to RECIST 1.1 criteria. Key secondary endpoints included objective response rate (ORR), overall survival (OS), and safety.
Results: A total of 203 patients with extrapancreatic NETs and 95 patients with pancreatic NETs were randomized.
- Extrapancreatic NET Cohort:
- Median PFS was 8.4 months with cabozantinib vs. 3.9 months with placebo (stratified hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.25–0.59; P<0.001).
- Partial responses were observed in 5% of patients receiving cabozantinib vs. 0% with placebo.
- Pancreatic NET Cohort:
- Median PFS was 13.8 months with cabozantinib vs. 4.4 months with placebo (stratified HR, 0.23; 95% CI, 0.12–0.42; P<0.001).
- Partial responses were observed in 19% of patients receiving cabozantinib vs. 0% with placebo.
Grade ≥3 treatment-related adverse events occurred in 62–65% of patients receiving cabozantinib and 23–27% receiving placebo. Common grade ≥3 adverse events included hypertension (21–22%), fatigue (11–13%), diarrhea (11%), and thromboembolic events (11%).
Conclusions: Cabozantinib significantly improved progression-free survival compared to placebo in patients with previously treated, progressive advanced extrapancreatic or pancreatic NETs. The safety profile was consistent with known adverse events associated with cabozantinib.
Implications for Practice:
- New Treatment Option: Cabozantinib offers a new therapeutic avenue for patients with advanced NETs who have progressed after prior therapies.
- Broad Applicability: The findings support the use of cabozantinib in both extrapancreatic and pancreatic NETs.
- Adverse Event Management: Clinicians should closely monitor and manage treatment-related adverse events to optimize patient outcomes.
Study Strengths and Limitations: Strengths include a large sample size, randomized controlled design, and inclusion of patients who had progressed after standard therapies, enhancing the applicability of the findings to clinical practice. Limitations involve early trial termination based on interim analysis, which may overestimate the treatment effect, the use of placebo rather than an active comparator, and the high rate of dose modifications due to adverse events.
Future Research: Further studies should explore the optimal sequencing of cabozantinib with other therapies in NETs and investigate combination treatments. Long-term studies assessing overall survival benefits and quality of life are warranted.