FDA Approves Cabozantinib for pNET and epNET in Patients 12+

On March 26, 2025, the U.S. Food and Drug Administration (FDA) granted approval for cabozantinib, marketed as Cabometyx by Exelixis, Inc., to be used in treating both adult and pediatric patients aged 12 and older who are battling previously treated, unresectable, locally advanced, or metastatic well-differentiated pancreatic neuroendocrine tumors (pNET) and extra-pancreatic neuroendocrine tumors (epNET). This marks a significant advancement in therapies for neuroendocrine tumors, a challenging category of cancers due to their complex nature and tendency to resist standard treatment protocols.

The efficacy of cabozantinib was thoroughly assessed through the CABINET trial (NCT03375320), a robust study designed as a double-blind, placebo-controlled, multicenter trial. It involved two distinct groups — one for pNET and another for epNET — encompassing a total of 298 participants whose conditions had worsened despite prior treatments. The primary measure of effectiveness was progression-free survival (PFS), which was carefully evaluated by a blinded independent radiology review committee following RECIST 1.1 criteria. Other measures of efficacy included overall response rate (ORR) and overall survival (OS).

In the pNET cohort, 99 patients were randomly assigned in a 2:1 ratio to receive either cabozantinib at a dosage of 60 mg orally once daily or a placebo, continuing until either disease progression or unacceptable toxicity occurred. Findings revealed a median PFS of 13.8 months in the cabozantinib group, compared to 3.3 months in the placebo group. The hazard ratio stood at 0.22, indicating a significantly lower risk of disease progression in patients treated with cabozantinib. The ORR was 18% in the cabozantinib group, contrasting with 0% in the placebo group. However, overall survival data were not fully mature at the time of analysis, with 48% of patients in the cabozantinib group and 52% in the placebo group having succumbed to the disease. Notably, over half of the patients receiving placebo transitioned to open-label cabozantinib, which might affect the clarity of overall survival statistics.

The epNET cohort included 199 individuals, following the same treatment regimen as the pNET group. Here, the median PFS was 8.5 months for those on cabozantinib, compared to 4.2 months for those on placebo. The hazard ratio was 0.40, supporting cabozantinib's capability to delay disease progression. The ORR for cabozantinib in this cohort was 5%, compared to 0% for placebo. Similar to the pNET cohort, the overall survival data were immature, with death rates at 63% for cabozantinib and 60% for placebo recipients, again noting a substantial crossover from placebo to cabozantinib treatment.

Cabozantinib's safety profile remained consistent with its established product label, offering guidance on its use. The recommended dosage for individuals aged 12 and older with a body weight of 40 kg or more is 60 mg orally daily, whereas those under 40 kg should receive 40 mg orally daily, until disease progression or unacceptable toxicity is observed.

This comprehensive review was conducted under Project Orbis, an initiative from the FDA Oncology Center of Excellence, aiming for simultaneous submission and review of oncology drugs across international partners. Collaborations included entities like the Australian Therapeutic Goods Administration (TGA) and Swissmedic from Switzerland, although reviews continue with these agencies. Utilizing rolling review and the FDA's Assessment Aid, the process was expedited to ensure timely access to this promising treatment option.

Healthcare providers are urged to report all severe adverse events potentially linked with the use of medications and medical devices to the FDA's MedWatch Reporting System.