FDA Approves Cabozantinib in Pancreatic/Extra-Pancreatic Neuroendocrine Tumors

Data from the phase 3 CABINET study support the approval of cabozantinib in patients with pancreatic neuroendocrine tumors.

The News

The FDA has approved cabozantinib (Cabometyx) as a treatment for adult and pediatric patients 12 years or older with previously treated, unresectable or locally advanced or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNETs) and well-differentiated extra-pancreatic NETs (epNETs), according to a press release from the FDA.¹

Supporting Data

The approval for cabozantinib was supported by findings from the phase 3 CABINET trial (NCT03375320), in which investigators evaluated the agent in patients with epNETs with a primary tumor arising in the gastrointestinal (GI) tract. Updated findings from a subgroup analysis were highlighted in a presentation at the 2025 ASCO Gastrointestinal Cancers Symposium.²

Analysis data revealed that among those in the NET cohort (n = 116), a median progression-free survival (PFS) of 8.5 months (95% CI, 6.0-16.7) was observed in patients assigned to the cabozantinib arm (n = 70) vs 5.6 months (95% CI, 3.9-11.0) in those assigned to placebo (n = 46; stratified HR, 0.50; 95% CI, 0.28-0.88; 1-sided stratified log rank P = .007). Additionally, in the respective arms, 1% vs 0% of patients experienced a confirmed partial response, with 69% vs 65% having stable disease, 9% vs 26% having progressive disease, and 21% vs 9% not being evaluable for response.

Further subgroup analyses revealed that a PFS benefit was observed among all clinical factor groups except for those with a non-midgut GI primary tumor site (HR, 2.38; 95% CI, 0.69-8.15). Those who experienced the most pronounced PFS benefit included those who had not received prior lutetium Lu-177 dotatate (Lutathera; HR, 0.19; 95% CI, 0.05-0.71), had grade 1 disease (HR, 0.30; 95% CI, 0.13-0.68), had an ECOG performance status score of 1 or 2 (HR, 0.32; 95% CI, 0.16-0.64), and who had a primary tumor site of midgut GI (HR, 0.35; 95% CI, 0.19-0.63).

Previous findings from CABINET reported in the New England Journal of Medicine showed that treatment with cabozantinib significantly improved PFS outcomes vs placebo in those with progressive advanced epNETs (stratified HR, 0.38; 95% CI, 0.25-0.59; P <.001) and pNETs (stratified HR, 0.23; 95% CI, 0.12-0.42; P <.001).³ Additionally, the confirmed objective response rates in the epNET and pNET subgroups, respectively, were 5% and 19%.

CABINET Trial Design

In the trial, the primary end point was PFS per RECIST v1.1 criteria via retrospective independent central review.⁴ Key secondary end points included radiographic response rate, overall survival, and safety.

In the most recent analysis of the CABINET trial, patients with grade 1 to 3 well- to moderately-differentiated epNETs or pNETs experiencing progressive disease within 12 months to random assignment following treatment with 1 or more FDA-approved systemic therapies, consisting of either everolimus (Afinitor), sunitinib (Sutent), or Lu-177 dotatate, were assessed. Patients were assigned to either the epNET arm or pNET arm and were randomly assigned 2:1 to receive 60 mg of once daily cabozantinib or placebo.

Among patients analyzed in the epNET subgroup, the median age was 66 years (range, 28-86) in those assigned to cabozantinib and 67 years (range, 42-78) in those assigned to placebo. In each respective arm, 49% vs 41% were female, 60% vs 50% had an ECOG performance status of 1, 47% vs 44% had a functional tumor, and 87% vs 80% received concurrent somatostatin analogs.

Disease grades 1, 2, and 3 accounted for 40% vs 28%, 54% vs 61%, and 4% vs 9% of respective arms, with unknown status reported in 1% vs 2% of each arm. Primary tumor sites encompassed jejunum, ileum, cecum, or appendix (59% vs 56%); small intestine or midgut/not otherwise specified (39% vs 17%); colon or rectum (10% vs 13%); stomach (4% vs 4%); and duodenum, ampullary, or biliary (1% vs 9%).

Patients received a median number of 1 prior therapy, excluding somatostatin analogs, in both the cabozantinib arm (range, 1-6) and placebo arm (range, 1-5). In each arm, 61% vs 54% of patients received prior everolimus, 79% vs 74% received prior Lu-177 dotatate, and 17% vs 15% received prior temozolomide (Temodar)–based therapies.

Safety Data

The safety profile of cabozantinib was consistent with previously reported data; 60% of the cabozantinib arm (n = 68) experienced grade 3 or 4 adverse events (AEs) vs 18% of the placebo arm (n = 45). The most common grade 3 or 4 AEs in each arm included hypertension (19% vs 4%), diarrhea (13% vs 4%), and fatigue (10% vs 4%). Grade 5 toxicities potentially linked to cabozantinib occurred in 3 patients, 2 of whom the cause of death was unspecified and the other experienced cardiac arrest.

The median duration of therapy was 5.8 months (range, 0.6-32.4) with cabozantinib vs 3.7 months (range, 0.6-21.4) with placebo. The average daily dose was 38.9 mg and 59.3 mg in the respective arms, with 13 vs 7 patients still undergoing treatment as of the data cutoff date of August 24, 2023. Treatment discontinuation occurred due to disease progression, AEs, withdrawn consent, and death on study, respectively, in 24, 16, 6, and 4 patients treated in the cabozantinib arm. In the placebo arm, 23 patients discontinued due to progressive disease, 5 due to AEs, and 4 due to withdrawn consent, with no discontinuations attributable to death on study.

The FDA previously accepted a supplemental new drug application (sNDA) for cabozantinib in patients with locally advanced/unresectable or metastatic, well- or moderately-differentiated pNETs or epNETs in August 2024.⁵

References

1. FDA approves cabozantinib for adults and pediatric patients 12 years of age and older with pNET and epNET. News release. FDA. March 26, 2025. Accessed March 26, 2025. https://tinyurl.com/chw5v9a8
2. Strosberg J, Zemla T, Geyer S, et al. Efficacy and safety of cabozantinib for advanced gastrointestinal (GI) neuroendocrine tumors (NET) after progression on prior therapy: subgroup analysis of the phase 3 CABINET trial (Alliance A021602). J Clin Oncol. 2025;43(suppl 4):666. doi:10.1200/JCO.2025.43.4_suppl.666
3. Chan JA, Geyer S, Zemla T, et al. Phase 3 trial of cabozantinib to treat advanced neuroendocrine tumors. N Engl J Med. Published online September 16, 2024. doi:10.1056/NEJMoa2403991
4. Testing cabozantinib in patients with advanced pancreatic neuroendocrine and carcinoid tumors. ClinicalTrials.gov. Updated January 13, 2025. Accessed January 30, 2025. https://tinyurl.com/2n4se9af
5. Exelixis announces U.S. Food and Drug Administration (FDA) accepted the supplemental New Drug Application for cabozantinib for patients with advanced neuroendocrine tumors. News release. Exelixis Inc. August 6, 2024. Accessed January 30, 2025. https://tinyurl.com/3fa29ust