Cabozantinib may be effective at improving progression-free survival in patients with previously treated neuroendocrine tumors, according to recent findings presented by Chan et al at the European Society for Medical Oncology (ESMO) Congress 2024 (Abstract 1141O) and simultaneously published in The New England Journal of Medicine.
“Although progress has been made in recent years, there remains a critical need for new and effective therapies for patients with advanced neuroendocrine tumors,” stressed lead study author 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.
Study Methods and Results
In the multicenter, randomized, double-blind phase III CABINET (A021602) trial (ClinicalTrials.gov identifier NCT03375320), researchers examined the efficacy of cabozantinib compared with placebo in two patient cohorts: those with advanced pancreatic neuroendocrine tumors (n = 95) and those with advanced extrapancreatic neuroendocrine tumors (n = 203). The extrapancreatic neuroendocrine tumor cohort included patients with the following primary tumor sites: gastrointestinal tract, lungs, unknown primary sites, and other.
To be included in the trial, the patients were required to have measurable disease per RECIST 1.1 criteria and to have experienced disease progression following at least one U.S. Food and Drug Administration (FDA)-approved line of prior therapy other than somatostatin analogs. The primary endpoint of the trial was progression-free survival in each cohort. Secondary endpoints included overall survival, radiographic response rate, and safety.
The researchers found the study met its primary objective for each cohort, demonstrating that cabozantinib may offer significant improvements in median progression-free survival in patients with pancreatic and extrapancreatic neuroendocrine tumors—based on blinded independent central review.
After a respective median follow-up of 13.8 months and 10.2 months, the patients in the pancreatic neuroendocrine tumor cohort who received cabozantinib experienced a median progression-free survival of 13.8 months vs 4.4 months (hazard ratio [HR] = 0.23, 95% confidence interval [CI] = 0.12–0.42, P < .0001). Those in the extrapancreatic neuroendocrine tumor cohort who received cabozantinib experienced a median progression-free survival of 8.4 months vs 3.9 months (HR = 0.38, 95% CI = 0.25–0.59, P < .0001) compared with the patients in both cohorts who received placebo.
Following additional analyses, the researchers revealed benefits with cabozantinib across all clinical subgroups examined—including primary tumor site, grade, and prior systemic anticancer therapy. In the patients with pancreatic neuroendocrine tumors, the objective response rate was 19% among those who received cabozantinib compared with 0% among those who received placebo. In the patients with extrapancreatic neuroendocrine tumors, the objective response rate by blinded independent central review was 5% among those who received cabozantinib compared with 0% among those who received placebo. Similar interim overall survival results for cabozantinib compared with placebo were observed in both cohorts (pancreatic neuroendocrine tumor cohort: HR = 0.95, 95% CI = 0.45–2.00; extrapancreatic neuroendocrine tumor cohort: HR = 0.86, 95% CI = 0.56–1.31).
The safety profile of cabozantinib in both cohorts was consistent with those reported in other studies examining the drug. The side effects included hypertension, fatigue, and diarrhea. No new safety signals were identified.
In August 2023, the Alliance Data and Safety Monitoring Board recommended that the study stop to be unblinded early as a result of the improvement in efficacy observed at an interim analysis in both trial cohorts. All patients were unblinded, and those on placebo were given the option to cross over to active treatment with cabozantinib. Cabozantinib demonstrated a statistically significant and clinically meaningful improvement in progression-free survival compared with placebo based on results of both on local review and on independent blinded central radiology review.
Conclusions
“Given 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,” highlighted Dr. Chan. “I’m encouraged by these final results showing that cabozantinib provided a clinically meaningful treatment benefit for patients with previously treated advanced neuroendocrine tumors, including across all major clinical subgroups. 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,” she underscored.
These study results were the basis of a supplemental new drug application (NDA) for cabozantinib for the treatment of adults with advanced neuroendocrine tumors. The FDA accepted the supplemental NDA in August 2024 and assigned a Prescription Drug User Fee Act target action date of April 3, 2025.
Disclosure: The research in this study was sponsored by the National Cancer Institute. For full disclosures of the study authors, visit cslide.ctimeetingtech.com and nejm.org.
