Exelixis Announces FDA Acceptance of Supplemental New Drug Application for Cabozantinib in Advanced Neuroendocrine Tumors

Exelixis, Inc. has announced that the U.S. Food and Drug Administration (FDA) has accepted its supplemental New Drug Application (sNDA) for cabozantinib, known commercially as CABOMETYX®. The application seeks approval for the treatment of adults with previously treated, locally advanced/unresectable or metastatic, well- or moderately differentiated pancreatic neuroendocrine tumors (pNET) and extra-pancreatic neuroendocrine tumors (epNET). Furthermore, the FDA has granted orphan drug designation to cabozantinib for the treatment of pNET. The Prescription Drug User Fee Act (PDUFA) target action date has been set for April 3, 2025, indicating when a decision is expected.

Amy Peterson, M.D., Executive Vice President of Product Development & Medical Affairs and Chief Medical Officer at Exelixis, expressed optimism regarding the FDA’s acceptance. She highlighted the significance of this development for patients with challenging cancer conditions who have limited treatment options. Peterson emphasized the company's eagerness to collaborate with the FDA to expedite the availability of this treatment option for patients suffering from advanced neuroendocrine tumors.

The data supporting the sNDA comes from the phase 3 CABINET trial, which evaluated cabozantinib against a placebo in two separate groups of patients with previously treated neuroendocrine tumors: advanced pNET and advanced epNET. Notably, the CABINET trial was halted early due to significant activity observed during an interim analysis, which showed a dramatic improvement in progression-free survival (PFS) for patients receiving cabozantinib compared to those on placebo. Consequently, all patients were unblinded, and those on placebo were given the option to switch to cabozantinib. The study demonstrated statistically significant and clinically meaningful improvements in PFS with cabozantinib, based on both local review and independent central radiology review. Initial results were shared at the 2023 European Society of Medical Oncology (ESMO) Congress, and final results are slated for presentation at the 2024 ESMO Congress in Barcelona, Spain.

The CABINET trial, a multicenter, randomized, double-blinded, placebo-controlled phase 3 study, enrolled 290 patients across the U.S. Patients were randomized in a 2:1 ratio to receive either cabozantinib or a placebo, with the trial divided into two cohorts: 93 patients with pNET and 197 with epNET. The epNET cohort included patients with primary tumors located in the gastrointestinal (GI) tract, lungs, and other sites. Each cohort had a separate statistical analysis plan. To be eligible, patients needed measurable disease as per RECIST 1.1 criteria and must have experienced disease progression or intolerance after at least one prior FDA-approved therapy, excluding somatostatin analogs. The primary endpoint for both cohorts was PFS, assessed by retrospective blinded independent central review. Upon disease progression, patients were unblinded, and those on placebo could switch to open-label cabozantinib treatment. Secondary endpoints included overall survival, radiographic response rate, and safety.

Neuroendocrine tumors (NET) are malignancies that originate in the specialized cells of the neuroendocrine system. These cells exhibit characteristics of both hormone-producing endocrine cells and nerve cells. In the United States, approximately 161,000 to 192,000 individuals are living with unresectable, locally advanced or metastatic NET. The incidence of NET diagnoses has been on the rise over the past few decades, with functional NETs known to release peptide hormones that cause severe symptoms such as diarrhea, hypertension, and flushing. Non-functional NETs primarily cause symptoms related to tumor growth. Although NETs tend to grow slowly, all patients with advanced or metastatic NET eventually develop refractory disease. NETs most commonly originate in the gastrointestinal tract or lungs, with pNETs being more aggressive.

For advanced NET patients, treatment options encompass somatostatin analogs, chemotherapy, targeted therapy, and peptide-receptor radionuclide therapy. CABOMETYX, while not currently indicated for NET, is approved in the U.S. for various cancers, including advanced renal cell carcinoma and hepatocellular carcinoma. The drug has also received regulatory approvals in other regions worldwide.