FDA Accepts sNDA for Cabozantinib in Pancreatic Neuroendocrine Tumors

FDA acceptance is based on phase 3 CABINET trial results, with cabozantinib showing a PFS improvement in patients with pancreatic neuroendocrine tumors.

The FDA has accepted a supplemental New Drug Application (sNDA) for cabozantinib (Cabometyx) in patients with locally advanced/unresectable or metastatic, well-, or moderately differentiated pancreatic neuroendocrine tumors (pNETs) or extra-pancreatic NETs (epNETs), according to a news release from the drug’s developer, Exelixis, Inc.¹

Cabozantinib was granted orphan drug designation by the FDA for pNET treatment. Additionally, a standard review was assigned by the FDA with an April 3, 2025 Prescription Drug User Free Act target date.

FDA acceptance of the sNDA is based on findings from the phase 3 CABINET trial (NCT03375320), where cabozantinib showed a statically significant and clinically meaningful improvement in progression-free survival (PFS) vs placebo in epNETs and pNETs by both local and independent blinded central radiology review. Results were presented at the 2023 European Society for Medical Oncology (ESMO) Congress.

Investigators found that among patients with epNET, median PFS was 8.2 months in the cabozantinib cohort and 3.2 months with placebo (stratified HR, 0.41; 95% CI, 0.27-0.62; P < .0001).² In patients with pNET, median PFS was 13.7 months and 3.0 months, respectively (stratified HR, 0.25; 95% CI, 0.12-0.49; P < .0001). No new safety signals were noted, with the Alliance Data and Safety Monitoring Board (DSMB) voting to terminate accrual and unblind patients on July 28, 2023.

"The FDA’s acceptance of this application marks another important milestone in our commitment to bringing cabozantinib to patients living with difficult-to-treat cancers and who have limited treatment options," Amy Peterson, MD, executive vice president of Product Development & Medical Affairs and chief medical officer of Exelixis, stated in a news release on the sNDA acceptance.¹ "We appreciate the opportunity to work with the FDA in the coming months as they review our application, with the goal to bring this new, effective treatment option to patients with advanced [NETs] as quickly as possible.”

Investigators of the double-blinded study randomly assigned patients 2:1 with locally advanced or metastatic well- or moderately differentiated pNETs (n = 197) or epNETs (n = 93) to receive 60 mg of cabozantinib once daily (n = 129, 62) or placebo (n = 68, 31) between October 2018 and June 2023. Randomization was stratified in the epNET cohort by concurrent somatostatin analog (SSA) and primary site and by concurrent SSA and prior sunitinib (Sutent) in the pNET cohort.

The primary end point was PFS, with preplanned interim analyses after 33% and 66% of events for futility. Secondary end points included response rate and overall survival—which were not included in efficacy analysis—and safety.

Median follow-up was 12.6 months in patients with epNETs and 10.1 months for those with pNETs. Independent DSMB interim analyses occurred after 50 events for patients with pNETs and 109 events for those with epNETs.

Grade 3 or greater adverse events (AEs) occurred in 94 (75.8%) of the cabozantinib cohort and 27 (42.9%) of the placebo cohort in patients with epNETs. Grade 3 or greater AEs were found in 41 (68.3%) and 13 (43.3%) of the experimental and control cohorts among patients with pNETs. A common grade 3 or greater AE was hypertension in 27.4% and 26.7% of the epNET and pNET cabozantinib cohorts and 4.8% and 20.0% of the placebo cohorts.

Inclusion criteria for the trial included progression within 12 months prior to registration and at least 1 prior therapy consisting of either everolimus, sunitinib, or Lu-177 dotatate (Lutathera).

References

1. Exelixis announces U.S. Food and Drug Administration (FDA) accepted the supplemental New Drug Application for cabozantinib for patients with advanced neuroendocrine tumors. News release. Exelixis Inc. August 6, 2024. Accessed August 7, 2024. https://tinyurl.com/3fa29ust
2. Chan J, Geyer S, Ou F-S, et al. Alliance A021602: Phase III, double-blinded study of cabozantinib versus placebo for advanced neuroendocrine tumors (NET) after progression on prior therapy (CABINET). Ann Oncol. 2023;34(suppl 2):S1292. doi:10.1016/j.annonc.2023.10.047