Jennifer A. Chan, MD, MPH

As reported in The New England Journal of Medicine by Chan et al, the multicenter phase III CABINET trial has shown significantly improved progression-free survival with the multitargeted tyrosine kinase inhibitor cabozantinib vs a placebo in previously treated patients with progressive, advanced extrapancreatic or pancreatic neuroendocrine tumors.

“The results support the use of cabozantinib as a new treatment option for patients with advanced extrapancreatic neuroendocrine tumors or pancreatic neuroendocrine tumors whose disease has progressed after at least one other line of therapy, not including somatostatin analogues, or in whom unacceptable side effects have developed after such therapy,” the investigators commented. “The choice of therapy should be individualized and based on the characteristics of the patient and the tumor.”

Study Details

The trial included patients with locally advanced or metastatic well or moderately differentiated extrapancreatic (n = 203) or pancreatic (n = 95) neuroendocrine tumors who previously underwent peptide receptor radionuclide therapy and/or targeted therapy. Within these tumor origin–defined cohorts, patients were randomly assigned in a 2:1 ratio to receive oral cabozantinib at 60 mg or placebo once daily.

The patients were required to have had disease progression or unacceptable toxicity leading to the discontinuation of treatment with at least one of the following U.S. Food and Drug Administration (FDA)-approved therapies: lutetium Lu-177 dotatate (Lu-177 dotatate) or everolimus in extrapancreatic neuroendocrine tumors (excluding lung neuroendocrine tumors); everolimus in lung neuroendocrine tumors; and Lu-177 dotatate, everolimus, or sunitinib in pancreatic neuroendocrine tumors.

The primary endpoint was blinded independent central review–assessed progression-free survival. Objective response, overall survival, and safety were evaluated as key secondary endpoints.

Progression-Free Survival

The median progression-free survival was longer in patients with extrapancreatic neuroendocrine tumors who were treated with cabozantinib vs the placebo (8.4 vs 3.9 months; stratified hazard ratio [HR] for disease progression or death = 0.38, 95% confidence interval [CI] = 0.25–0.59; P < .001). In those with pancreatic neuroendocrine tumors, the median progression-free survival was 13.8 months with cabozantinib vs 4.4 months with the placebo (stratified HR = 0.23, 95% CI = 0.12–0.42; P < .001).  

The confirmed objective response rates with cabozantinib were 5% and 19%, respectively, in the patients with extrapancreatic and pancreatic neuroendocrine tumors; in both cohorts, the rate was 0% with the placebo.

“No overall survival difference between the trial groups has been observed to date,” the investigators remarked. “However, overall survival data were not mature at the time of the analyses and may have been affected by crossover [(extrapancreatic: 33%; pancreatic: 41%)] and by the high rate of treatment with subsequent anticancer therapies [(cabozantinib and placebo, extrapancreatic: 45% and 67%; pancreatic: 51% and 62%)].”

Safety Summary

Treatment-related adverse events of grade 3 or higher were observed with cabozantinib vs the placebo in 62% vs 27% of the patients with extrapancreatic neuroendocrine tumors and 65% vs 23% of those with pancreatic neuroendocrine tumors, respectively. Hypertension (extrapancreatic: 21%; pancreatic: 22%), fatigue (extrapancreatic: 13%; pancreatic: 11%), diarrhea (extrapancreatic: 11%), and thromboembolic events (pancreatic: 11%) were among the most frequently reported treatment-related adverse events of grade 3 or 4 with cabozantinib.

The investigators concluded: “Cabozantinib, as compared with placebo, resulted in longer progression-free survival in patients with extrapancreatic neuroendocrine tumors or pancreatic neuroendocrine tumors that had progressed after previous therapy with Lu-177 dotatate or targeted agents, including everolimus or sunitinib. Adverse events, which were managed with dose reduction in a majority of the patients, were consistent with the known safety profile of cabozantinib.” They added that clinical trials evaluating the appropriate sequencing of therapy are needed.

Disclosure: The study was funded by grants from the National Cancer Institute of the National Institutes of Health and Exelixis. For full disclosures of the study authors, visit nejm.org.