The Alliance for Clinical Trials in Oncology today announced final results will be presented at ESMO 2024 from CABINET (A021602), a phase III trial evaluating cabozantinib compared with placebo in two cohorts of patients with previously treated neuroendocrine tumors: one cohort of patients with advanced pancreatic neuroendocrine tumors (pNET) and a second cohort of patients with advanced extra-pancreatic NET (epNET). The study met the primary objective for each cohort, demonstrating that cabozantinib provided dramatic improvements in median progression-free survival (PFS) for the patients in the pNET and epNET cohorts. The data are being presented today at 7:45 am CT/2:45 pm CEST during the Proffered Paper Session - NETs and Endocrine Tumours (1141O) at the 2024 European Society of Medical Oncology (ESMO) Congress by Alliance Study Chair Jennifer Chan, MD, MPH, and were simultaneously published in the New England Journal of Medicine (NEJM)].
"Although progress has been made in recent years, there remains a critical need for new and effective therapies for patients with advanced neuroendocrine tumors. 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. Chan, Clinical Director of the Gastrointestinal Cancer Center and Director of the Program in Carcinoid and Neuroendocrine Tumors at Dana-Farber Cancer Institute. "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."
Final results from the CABINET study presented today at ESMO and published in NEJM demonstrate that treatment with cabozantinib resulted in compelling improvements in progression-free survival (PFS) based on blinded independent central review (BICR). In the pNET cohort, at a median follow-up of 13.8 months, median PFS was 13.8 months for cabozantinib versus 4.4 months for placebo (hazard ratio (HR) was 0.23 [95% confidence interval (CI): 0.12-0.42] p<0.0001). In the epNET cohort, at a median follow-up of 10.2 months, median PFS was 8.4 months versus 3.9 months for placebo (HR was 0.38 [95% CI: 0.25-0.59] p<0.0001]).
Additional analyses suggest 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 with 0% with placebo. In the epNET cohort, the ORR by BICR was 5% with cabozantinib compared with 0% with placebo. Similar interim overall survival results for cabozantinib compared to placebo were observed in both cohorts; HRs of overall survival were 0.95 (95% CI: 0.45-2.00) for the pNET cohort and 0.86 (95% CI: 0.56-1.31) for the epNET cohort.
The safety profile of cabozantinib observed in each cohort was consistent with those found in other studies of the drug. Side effects include hypertension, fatigue, and diarrhea. No new safety signals were identified.
These results were the basis of a supplemental new drug application (sNDA) for cabozantinib for the treatment of adults with advanced NET submitted by Exelixis. The U.S. Food and Drug Administration (FDA) accepted the sNDA in August and assigned a Prescription Drug User Fee Act target action date of April 3, 2025.
In August 2023, the Alliance Data and Safety Monitoring Board (DSMB) recommended the study stop and be unblinded early due to the dramatic improvement in efficacy observed at an interim analysis in both of the trial's 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 PFS versus placebo based on results of both on local review and on independent blinded central radiology review. Initial results from the study's principal investigator, Dr. Chan, were presented at ESMO 2023.
CABINET (randomized, double-blinded phase III study of CABozantinib versus placebo In patients with advanced NEuroendocrine Tumors after progression on prior therapy) is a multicenter, randomized, double-blinded, placebo-controlled phase III pivotal trial. This trial enrolled 298 patients in two separate cohorts (pNET, n=95; epNET, n=203) in the United States. The epNET cohort included patients with the following primary tumor sites: gastrointestinal (GI) tract, lung, unknown primary sites, and other. Patients were randomized 2:1 into the cabozantinib or placebo arms of the study in each of the two cohorts. Patients must have had measurable disease per RECIST 1.1 criteria and must have experienced disease progression after at least one FDA-approved line of prior therapy other than somatostatin analogs. The primary endpoint was PFS in each cohort. Upon confirmation of disease progression, patients were unblinded, and those receiving placebo were permitted to cross over to open-label therapy with cabozantinib. Secondary endpoints included overall survival, radiographic response rate and safety.
CABINET is sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, and is being led and conducted by the NCI-funded Alliance for Clinical Trials in Oncology with participation from the NCI-funded national clinical trials network (NCTN) as part of Exelixis' collaboration with the National Cancer Institute's Cancer Therapy Evaluation Program (NCI-CTEP). To learn more about the CABINET trials, visit ClinicalTrials.gov.
