Exelixis, Inc. (Nasdaq: EXEL) announced that the U.S. Food and Drug Administration (FDA) has scheduled a discussion of the supplemental New Drug Application (sNDA) for cabozantinib (CABOMETYX®) at an Oncologic Drugs Advisory Committee (ODAC) meeting in March 2025. The sNDA seeks approval for treating adults with previously treated advanced pancreatic neuroendocrine tumors (pNET) and advanced extra-pancreatic neuroendocrine tumors (epNET). This application is based on the final results of the Phase 3 CABINET trial, conducted by the National Cancer Institute’s National Clinical Trials Network. In August 2024, Exelixis also announced that the FDA granted orphan drug designation for cabozantinib for pNET, with a Prescription Drug User Fee Act action date of April 3, 2025.
The CABINET trial, which enrolled 298 patients, compared cabozantinib (60 mg) to placebo for advanced pNET and epNET, showing significant improvements in progression-free survival (PFS). The trial halted early based on a recommendation from the Alliance for Clinical Trials in Oncology’s independent Data and Safety Monitoring Board due to the positive results. Final data, presented at the 2024 European Society of Medical Oncology Congress and published in the New England Journal of Medicine, confirmed the benefit of cabozantinib.
ODAC will review the safety and effectiveness of cabozantinib in treating these cancers. However, this review is unrelated to the current approved uses of CABOMETYX in the U.S.
About CABINET (Alliance A021602)
CABINET is a Phase 3, randomized, double-blind, placebo-controlled study evaluating cabozantinib in patients with advanced neuroendocrine tumors (NET) after progression on prior therapy. The trial includes separate cohorts for pNET (n=95) and epNET (n=203), with a primary endpoint of PFS per RECIST 1.1, and secondary endpoints assessing overall survival, response rate, and safety.
About Neuroendocrine Tumors (NET)
NETs are cancers originating in the neuroendocrine system, which shares traits with both hormone-producing endocrine cells and nerve cells. NETs can develop in various body parts, including the gastrointestinal tract, lungs, and pancreas. Treatment for advanced NET includes somatostatin analogs, chemotherapy, targeted therapy, and peptide-receptor radionuclide therapy.
About CABOMETYX® (cabozantinib)
CABOMETYX is approved for the treatment of advanced renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and locally advanced or metastatic differentiated thyroid cancer (DTC). It is also authorized in over 65 countries outside the U.S. and Japan. Exelixis holds exclusive rights to develop and commercialize cabozantinib in the U.S.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
- Hemorrhage: Severe and fatal hemorrhages have occurred with CABOMETYX. The incidence of Grade 3-5 hemorrhagic events was 5% in patients with RCC, HCC, and DTC. Discontinue CABOMETYX for Grade 3 or 4 hemorrhages and before surgery. Avoid CABOMETYX in patients with a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
- Perforations and Fistulas: Fistulas and GI perforations, including fatal cases, occurred in 1% of patients. Monitor for signs of fistulas and perforations (e.g., abscess, sepsis). Discontinue CABOMETYX in patients with Grade 4 fistulas or GI perforations.
- Thrombotic Events: CABOMETYX increases the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism), and arterial thromboembolism in 2%. Fatal thrombotic events have been reported. Discontinue CABOMETYX in patients with acute myocardial infarction or serious thromboembolic events.
- Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension occurred in 37% of patients (16% Grade 3, <1% Grade 4). Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly and withhold CABOMETYX if hypertension cannot be controlled; resume at a reduced dose once controlled. Permanently discontinue for severe, uncontrollable hypertension or hypertensive crisis.
- Diarrhea: Diarrhea occurred in 62% of patients, with 10% experiencing Grade 3. Manage with antidiarrheals, and withhold CABOMETYX until diarrhea improves to ≤ Grade 1; resume at a reduced dose.
- Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of patients, with 13% experiencing Grade 3. Withhold CABOMETYX until PPE improves to Grade 1; resume at a reduced dose for Grade 2 or Grade 3 PPE.
- Hepatotoxicity: CABOMETYX combined with nivolumab can cause hepatic toxicity, with higher rates of ALT and AST elevations. Monitor liver enzymes before and during treatment. Interrupt treatment if enzyme levels rise; consider corticosteroids if necessary.
- Adrenal Insufficiency: CABOMETYX with nivolumab can cause adrenal insufficiency. For Grade 2 or higher, initiate hormone replacement therapy. Withhold CABOMETYX and/or nivolumab, and resume at a reduced dose based on severity.
- Proteinuria: Proteinuria occurred in 8% of patients. Monitor urine protein regularly. Withhold CABOMETYX for Grade 2 or 3 proteinuria until it improves to ≤ Grade 1, and resume at a reduced dose. Discontinue for nephrotic syndrome.
- Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of patients. Perform an oral exam before and during treatment. Advise good oral hygiene and withhold CABOMETYX for at least 3 weeks before dental surgery. Resume at a reduced dose after ONJ resolution.
- Impaired Wound Healing: CABOMETYX can cause wound complications. Withhold for at least 3 weeks before elective surgery and 2 weeks after major surgery until healing occurs. The safety of resuming treatment after wound complications has not been established.
- Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, characterized by subcortical vasogenic edema on MRI, can occur with CABOMETYX. Discontinue treatment if RPLS develops.
- Thyroid Dysfunction: Hypothyroidism was observed in 19% of patients. Monitor thyroid function before and during treatment and manage any dysfunction as needed.
- Hypocalcemia: Hypocalcemia occurred in 13% of patients, with Grade 3 in 2% and Grade 4 in 1%. Monitor blood calcium levels and replace calcium as necessary. Withhold and resume at a reduced dose or permanently discontinue based on severity.
- Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 4 months after the last dose. Verify pregnancy status before initiating treatment.
