FDA Approval of Cabozantinib for Pancreatic and Extra-Pancreatic Neuroendocrine Tumors Opens the Door to a New Standard Option

Jennifer Chan, MD, MPH

Options for later lines of neuroendocrine tumor treatment were limited until the FDA approved cabozantinib (Cabometyx), which helped change the narrative for adult and pediatric patients aged 12 years or older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET) and well-differentiated extra-pancreatic neuroendocrine tumors (epNET), according to Jennifer Chan, MD, MPH.

The March 26, 2025, FDA approval was based on data from the phase 3 CABINET trial (NCT03375320), which evaluated the efficacy and safety of cabozantinib vs placebo in patients with unresectable, locally advanced, or metastatic pNET/epNET that had progressed on prior treatment (n = 298). The study included pNET (n = 99) and epNET (n = 199) cohorts, which randomly assigned the respective patients 2:1 to receive either cabozantinib or placebo.1

“To have an [FDA approval cover a] broad range of primary tumor sites is wonderful to see, as it also covers patients who have functional tumors or nonfunctional tumors, and those who may have somatostatin receptor–positive or –negative disease,” Chan said in an interview with OncLive®. “There weren’t many restrictions in the approval, which means that it’s [now] a standard option for a large number of patients.”

In the pNET cohort, the median progression-free survival (PFS) was 13.8 months (95% CI, 8.9-17.0) vs 3.3 months (95% CI, 2.8-5.7) in the cabozantinib and placebo arms, respectively (HR, 0.22; 95% CI, 0.12-0.41; P <.0001). Of note, the overall response rate (ORR) was 18% (95% CI, 10%-30%) vs 0% (95% CI, 0%-11%) in the respective arms. A total of 52% of patients crossed over from the placebo arm to the open-label cabozantinib arm. In the epNET cohort, the median PFS was 8.5 months (95% CI, 6.8-12.5) vs 4.2 months (95% CI, 3.0-5.7) in the cabozantinib and placebo arms, respectively (HR, 0.40; 95% CI, 0.26-0.61; P <.0001). The ORR was 5% (95% CI, 2.2%-11%) vs 0 (95% CI, 0%-5%) in the respective arms. Notably, 37% of patients from the placebo arm crossed over to open label cabozantinib.

During the interview, Chan highlighted how the approval of cabozantinib addressed unmet needs and provided advice on managing cabozantinib-related adverse effects (AEs) based on the known safety profile. Chan is the clinical director of the Gastrointestinal Cancer Center and director of the Program in Carcinoid and Neuroendocrine Tumors at Dana-Farber Cancer Institute, and associate professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

OncLive: What is the significance of this FDA approval of cabozantinib?

Chan: First, this is good news for patients [with pNET or epNET] and clinicians who take care of patients with this diagnosis. We have needed newer treatments for patients with neuroendocrine tumors, particularly for patients who have had other lines of therapy and [experienced disease progression]. This approval means we have a new standard option to offer patients with neuroendocrine tumors who’ve had at least 1 other line of therapy and whose disease is progressing and needs additional therapy to control [disease] growth.

What unmet needs does this approval address?

The first unmet need was more treatment options, particularly for patients whose disease continued to progress. Some of these patients may not have other standard options or may not be candidates for some of the other options we have. One of the biggest unmet needs has been, for instance, in patients with epNETs, who didn’t have a TKI as a standard option. In patients with pNETs, sunitinib [Sutent] is an FDA approved option. However, in the epNET cohort, there have been more limited options. In addition to that breakdown of epNET and pNETs, there aren’t restrictions in terms of just lung and gastrointestinal [sites]; [the approval] broadened in that range, because there are some patients, particularly with the more rare neuroendocrine tumors, like thymus neuroendocrine tumors, where it might not have been covered in another indication, and some of those patients might have had more difficulty getting treatment. This [approval] is not as restrictive.

What did CABINET evaluate, and what were the enrollment criteria?

This was a randomized, phase 3 trial of cabozantinib compared with placebo in patients with advanced neuroendocrine tumors who received prior therapy. If you break the trial design down a bit more, it had 2 cohorts of patients, and each of these cohorts was independent, so it was essentially 2 trials in 1. There was a group of patients with epNETs and a group of patients with pNETs. All patients had to have had disease progression on at least 1 prior therapy. The goal of the trial was really to establish and investigate the efficacy of cabozantinib in this patient population. We had designed the trial specifically to look at PFS as the primary end point, to assess how cabozantinib could slow [tumor] growth. The results of the trial, which we reported at the end of 2024, showed that cabozantinib, in both groups of patients, improved PFS compared with placebo. Specifically, in patients who had epNETs, there was a 62% reduction in the risk of disease progression or death compared with placebo (stratified HR for progression or death, 0.38; 95% CI, 0.25-0.59; P <.001).2 In the pNET cohort, there was a 77% reduction in disease progression or death (stratified HR, 0.23; 95% CI, 0.12-0.42; P <.001).

What were the key safety data?

Safety was also an important end point of the study, and it did not show that cabozantinib had any new safety signals. The AEs that we observed in patients enrolled on the trial were very similar to what has been observed with cabozantinib when it’s been used to treat [patients with] other diseases. The most common AEs observed included hypertension, fatigue, diarrhea, and lower-grade elevations and liver function tests. The higher-grade AEs also included hypertension, diarrhea, fatigue, and in the patients who had pNETs, there were thromboembolic events observed as one of the higher-grade AEs. These are the known safety signals with cabozantinib; therefore, it was encouraging not to see anything we weren’t already aware of when we used it in other diseases.

What advice do you have about managing these AEs?

It’s important to be on the lookout for these AEs. One of the key things about using this to treat patients with neuroendocrine tumors is recognizing that in a large number of patients, there will be a need to pause treatment or reduce the dose. In the trial, we started out with a dose of 60 mg daily, but most patients did require a dose reduction to 40 mg or even 20 mg, if needed. There were some overlapping AEs, and some of our patients were already more susceptible to some of them. It’s important to monitor for [AEs, such as] diarrhea, hypertension, fatigue, and those [other] common ones.

References

1. FDA approves cabozantinib for adults and pediatric patients 12 years of age and older with pNET and epNET. FDA. March 26, 2025. Accessed April 23, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-cabozantinib-adults-and-pediatric-patients-12-years-age-and-older-pnet-and-epnet
2. Chan JA, Geyer S, Zemla T, et al. Phase 3 trial of cabozantinib to treat advanced neuroendocrine tumors. N Engl J Med. 2025;392(7):653-665. doi:10.1056/NEJMoa2403991