FDA Approval of Cabozantinib in Neuroendocrine Tumors

Aman Chauhan, MD University of Miami

Key Points

• Cabozantinib improved median progression-free survival (PFS) in patients with advanced neuroendocrine tumors (NETs) in the phase 3 CABINET trial.

• Sequencing cabozantinib will differ patient to patient, but it’s likely to slot in as a third-line treatment for pancreatic NETs.

• Tyrosine kinase inhibitor (TKI)–related adverse events need to be distinguished from symptoms of the underlying NET to optimize toxicity management

The hosts of the Oncology Brothers podcast, Drs. Rahul Gosain and Rohit Gosain, spoke with Aman Chauhan, MD, of Sylvester Comprehensive Cancer Center in Miami, Florida, to discuss using cabozantinib in patients with advanced NETs.

The US Food and Drug Administration (FDA) expanded the approved indications for cabozantinib on March 26, 2025, to include previously treated, advanced NETs based on data from the CABINET trial.

CABINET Trial Design

The phase 3 randomized clinical trial compared cabozantinib with placebo in patients with previously treated advanced pancreatic and extrapancreatic NETs. The primary end point was median PFS, and additional end points included response rates, overall survival (OS), and quality of life.

The cabozantinib starting dose was 60 mg daily, with dose reductions allowed in the event of toxicity. Patients in the placebo arm could switch to cabozantinib if they had disease progression.

CABINET was notable for including patients with lung NETs, which are often not included in NET trials, Dr. Chauhan said. Additionally, CABINET enrolled patients with grade 2, higher grade 2, and grade 3 well-differentiated NETs. Dr. Chauhan noted that grade 3 well-differentiated NETs are a newer stratification, and older trials have not formally investigated their biology.

Dr. Rohit Gosain commented on the use of a placebo control in the trial, which Dr. Chauhan agreed was not ideal. However, he noted that including patients with lung NETs limited the number of approved therapies that could be used as comparators. “I do feel that this was a well-designed study, and placebo control was ethical for this space at that time of design,” he said.

CABINET Trial Findings

According to Dr. Chauhan, cabozantinib was expected to show the greatest benefit in pancreatic NETs, as previous anti-VEGF TKI trials had shown promise for pancreatic NETs. 

Indeed, in pancreatic tumors, the median PFS with cabozantinib was 13.8 months (95% CI, 9.2-18.5) compared with 4.4 months (95% CI, 3.0-5.9) with placebo (hazard ratio [HR], 0.23; 95% CI, 0.12-0.42; P < .001). In extrapancreatic tumors, the median PFS was 8.4 months (95% CI, 7.6-12.7) with cabozantinib versus 3.9 months (95% CI, 3.0-5.7) with placebo (HR, 0.38; 95% CI, 0.25-0.59; P < .001).

Although cabozantinib did not show a statistically significant improvement in OS, Dr. Chauhan stated that it’s difficult to see an OS benefit in indolent cancers like NETs. “I take the overall survival data with a grain of salt when it comes to neuroendocrine tumors; however, median PFS is a great surrogate end point,” he said. “We have seen how median PFS has led to FDA approvals and has led to improvement in overall survival of our neuroendocrine cancer patients over the last 10 years.”

Sequencing Cabozantinib in NETs

Shifting from trial findings to real-world implementation, Dr. Rahul Gosain asked what the appropriate sequencing is for cabozantinib. Dr. Chauhan suggested that, given the heterogeneous nature of NETs, there is no straightforward algorithm, and treatment must be tailored to each tumor.

Generally, almost all patients with pancreatic NETs would have received at least a somatostatin analogue (SSA). Peptide receptor radionuclide therapy (PRRT) has also solidified itself as a go-to second line for most patients based on data regarding its efficacy, comfort level, and quality-of-life improvement.

For pancreatic NETs, “I see cabozantinib entering the third-line space and leaving a lot of plan B options for us, be it [everolimus] or sunitinib, [capecitabine and temozolomide], et cetera,” Dr. Chauhan said. 

He added that he has been using cabozantinib more in patients who have been retreated off-label with PRRT after exhausting capecitabine and temozolomide. “Cabozantinib is not as tough on marrow as compared to [capecitabine and temozolomide] and PRRT,” he said, “and has really helped rescue a lot of my patients and stabilize their cancer in those scenarios.”

Sequencing cabozantinib can differ for lung NETs, as many patients won’t express somatostatin receptors, precluding the use of SSA or PRRT. Dr. Chauhan suggested that everolimus then cabozantinib may be an appropriate strategy.
Comparatively, for grade 3 well-differentiated NETs, the NETTER-2 trial established PRRT as a preferred frontline therapy. For patients with rapid tumor growth, starting chemotherapy immediately is not a bad choice, according to Dr. Chauhan. For higher-grade tumors, he said, “I foresee [cabozantinib] is going to start moving behind PRRT but above other targeted therapies.”

Managing Adverse Effects of Cabozantinib 

Dr. Rahul Gosain noted that cabozantinib also carries the classwide adverse effects seen with TKIs, including gastrointestinal (GI) adverse effects and hypertension. He cautioned that because some GI adverse effects can mimic the symptoms of advanced NETs, it’s important to identify whether events are TKI related or disease related to optimize management.

Deviating from the CABINET trial, Dr. Chauhan said he personally prefers to start cabozantinib at a dose of 40 mg to reduce toxicity and then increase it, based on the patient’s response. “In my experience, the majority of patients only tolerate 40 mg, if that,” he said. “Sometimes I have to reduce the dose from 40 mg to 20 mg.”

Dr. Chauhan also suggested that cabozantinib uptake might be easier for community oncologists, as they may already be using this agent for its other cancer indications.

Closing the call, Dr. Chauhan stated that the approval of cabozantinib for NETs “is a big step forward in the neuroendocrine oncology field.”