Behind the FDA Approval: Cabozantinib for Advanced Neuroendocrine Tumors

Jennifer Chan, MD, MPH

Clinical Director, Gastrointestinal Cancer Center

Director, Program in Carcinoid and Neuroendocrine Tumors

Dana-Farber Cancer Institute

Boston, MA

Patients treated for advanced neuroendocrine tumors (NETs) are at risk of disease progression after existing treatments, and the current options are often dependent on particular disease factors that vary depending on the location and grade of disease. The FDA’s recent approval of cabozantinib (Cabometyx) provides a new option with evidence supporting its use in both pancreatic neuroendocrine tumors (pNETs) and extrapancreatic neuroendocrine tumors (epNETs).¹

“We have a new treatment option to slow disease progression, and this cuts across a very wide in group of patients with NETs, regardless of primary tumor site and regardless of other clinical factors,” said Jennifer Chan, MD, MPH. “The impact for patients who are coming into our clinics with this diagnosis is quite broad, and that's really encouraging.”

In an interview with Targeted Oncology, Chan, who is clinical director at the Gastrointestinal Cancer Center and director for the Program in Carcinoid and Neuroendocrine Tumors at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School, discussed the findings from the phase 3 CABINET trial (NCT03375320) that led to the FDA approval.

The randomized, double-blind phase 3 CABINET trial enrolled 203 patients with epNETs and 95 with pNETs to receive cabozantinib or placebo on a 2:1 basis. Cabozantinib showed superiority in its primary end point of progression-free survival (PFS) in both cohorts in an interim analysis. This led to the Data and Safety Monitoring Board recommending early termination, after which patients were unblinded and crossover permitted.²

In the interview, Chan discussed the rationale for the trial, the importance of the outcomes, and what significance this has for patients with advanced NETs.

Targeted Oncology: What is the background of the CABINET trial in patients with NETs?

Jennifer Chan, MD, MPH: The CABINET trial was based on a phase 2 trial [NCT01466036] that was conducted at Dana-Farber Cancer Institute and at Massachusetts General Hospital. The basic background for the trial is that NETs are very vascular tumors, and one of the strategies for treating NETs is to block angiogenesis. One of the mechanisms by which you can do this is with a tyrosine kinase inhibitor like cabozantinib that inhibits VEGF, the vascular endothelial growth factor receptor, and other tyrosine kinase receptors—particularly MET, which is one of the mechanisms for resistance that may develop to VEGF pathway inhibition. We have seen very encouraging results from the phase 2 trial. There was a response rate in 15% in both the pNET and epNET [groups] and also encouraging PFS.³

These results led to the development of the CABINET trial, and that was a phase 3 trial that was NCI [National Cancer Institute] sponsored and conducted by the Alliance for Clinical Trials in Oncology across the NCI's National Clinical Trials Network. It was a randomized, double-blinded, placebo-controlled trial of cabozantinib vs placebo. There were 2 cohorts of patients. The first were patients who had NETs starting in the pancreas, and then there was a cohort of patients that had epNETs. This primarily included lung NETs and gastrointestinal [GI] NETs, but all of the patients who enrolled had had at least 1 prior line of FDA-approved therapy, so the trial was designed to see if we could prove efficacy of cabozantinib in patients who were needing an additional option to control disease progression.

What were the key findings from this trial that led to the FDA approval?

The primary outcome was PFS, and the trial was stopped early in August 2023 based on an interim analysis that showed superiority for cabozantinib vs placebo. In both groups of patients, [there was] an improvement in PFS. Specifically in the cohort of patients who had pNETs, there was a 77% reduction in the risk of disease progression or death, and in the epNET cohort of patients, there was a 62% reduction in disease PFS.²

What we published was the cohorts in terms of how patients were allocated and [randomly assigned] in the study. So that was 203 and 95 in the manuscript. When you look at the FDA announcement…there were some patients [with] pNET who were incorrectly assigned to the epNET [cohort]. They are looking at their data from the diagnosis standpoint, as opposed to what we had done for the analysis, which was the design of the trial based on how patients were put into the various cohorts. That's where those small differences come into play, where there were some patients with pNET as a diagnosis who got incorrectly assigned into the epNET cohort and vice versa.^1,2

Were there any safety outcomes with cabozantinib that were unexpected?

There were no unexpected adverse events [AEs].² What we observed for safety was very consistent with what has been observed for cabozantinib in other disease settings. Some of the common AEs that we observed in patients who were receiving cabozantinib have included, for instance, hypertension, diarrhea, and] fatigue. In some of the higher-grade AEs, the more serious AEs again [were] overlapping where it was also hypertension, diarrhea, fatigue, and in patients with pNETs, there were thromboembolic AEs that we observed, but these were not new safety signals.

How did the outcomes differ in the pNET vs epNET cohorts?

The epNET cohort was the larger cohort of patients. There were a smaller number of patients with pNETs, but from the patients who were enrolled, we did see a higher objective response rate in patients who had pNETs. The objective response rate in the pNET patients was 19% and it was 5% in the epNET patients. There was that response signal that seemed higher in the pNETs, and the HR for PFS was also stronger in the pNET cohort. Exactly what is driving that, we don't know. We do know that there are biological differences between pNETs and GI NETs and lung NETs. Although they all fall under that umbrella of diagnosis of NETs, there are differences in the genomics, the prognosis, and even sensitivity to therapy. What we're seeing with cabozantinib in the CABINET trial is probably based on some of these biological differences.

What is the most promising thing about the use of cabozantinib in this setting?

What's really promising, and I think what's good news for our patients, is that we have a new treatment option to slow disease progression, and this cuts across a very wide in group of patients with NETs, regardless of primary tumor site and regardless of other clinical factors. It didn't necessarily depend on somatostatin receptor expression or whether tumors were functional or nonfunctional. The impact for patients who are coming into our clinics with this diagnosis is quite broad, and that's really encouraging,

How does cabozantinib fit into the landscape of existing therapies for NETs?

It is a newer option to consider. We have a number of options that can be used in clinical practice for advanced NETs. There are the somatostatin analogs, which for many patients with grade 1 or grade 2 NETs of the GI tract and pancreas, we often start with that approach first. Then beyond somatostatin analogs, there are a number of options: radionuclide therapy targeting the somatostatin receptor, molecularly targeted therapies, and cabozantinib is another one to consider, in addition to everolimus, and for pNETs, sunitinib [Sutent]. There is also a subset of patients with pNETs or even lung NETs where we might consider cytotoxic chemotherapy.

There is still a lot of work that needs to be done to try to understand optimal sequencing of all these agents, and there have recently been some trials that have reported out results of randomized studies comparing, for instance, radionuclide therapy with a targeted agent. But…we have another option to consider, and what's also encouraging for patients is that although we may not necessarily know the optimal choice and sequencing of therapy, we have more options to consider. For instance, particularly for patients whose disease has progressed on 1 therapy, there is often a need to switch to something else. Having it as an option is really encouraging.

What next steps are being taken by investigators in this setting?

We have correlative work that is planned in the CABINET trial. We will hopefully be presenting the results of quality-of-life studies for patients who are enrolled in the trial. That's an important consideration as we think not just about the efficacy of therapy, but the impact of treatment on patients. There also will be work that is being done to look at potential biomarkers that may predict responsiveness to treatment, for instance at the tissue biomarker level or plasma biomarker level. We are also looking forward to doing a deeper dive into the radiology studies and looking at potential radiology signals of treatment efficacy.

_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 March 31, 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}

_{3. Chan JA, Faris JE, Murphy JE, et al. Phase II trial of cabozantinib in patients with carcinoid and pancreatic neuroendocrine tumors (pNET). J Clin Oncol. 2017;35(suppl 4):228. doi:10.1200/JCO.2017.35.4_suppl.228.}