FDA Approves Cabozantinib for Pancreatic and Extra-Pancreatic Neuroendocrine Tumors

FDA

The FDA has approved cabozantinib (Cabometyx) for the treatment of 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).1,2

The regulatory decision is supported by findings from 2 cohorts of the phase 3 CABINET trial (NCT03375320). In the pNET cohort (n = 99), the agent (n = 66) led to a median progression-free survival (PFS) of 13.8 months (95% CI, 8.9-17.0) vs 3.3 months (95% CI, 2.8-5.7) with placebo (n = 33; HR, 0.22; 95% CI, 0.12-0.41; P < .0001). The overall response rate (ORR) with cabozantinib was 18% (95% CI, 10%-30%) vs 0% (95% CI, 0%-11%) with placebo. The median duration of response (DOR) was 11.4 months (95% CI, 6.1-not evaluable [NE]) in the cabozantinib arm vs NE in the placebo arm. Overall survival (OS) data were not mature (HR, 1.01).

In the epNET cohort (n = 199), cabozantinib (n = 132) led to a median PFS of 8.5 months (95% CI, 6.8-12.5) vs 4.2 months (95% CI, 3.0-5.7) with placebo (n = 67; HR, 0.40; 95% CI, 0.26-0.61; P < .0001). The respective ORRs were 5% (95% CI, 2.2%-11%) and 0% (95% CI, 0%-5%). The median DOR in the respective arms was 8.3 months (95% CI, 4.5-NE) and NE. OS data were not mature in this cohort either (HR, 1.01).

Taking a Closer Look at CABINET: Design, Population, Objectives

The randomized, double-blind, placebo-controlled, multicenter study enrolled patients with unresectable, locally advanced or metastatic pNET or epNET who had progressed on previous therapy. Patients must have previously received at least 1 FDA-approved therapy such as everolimus (Afinitor), sunitinib (Sutent), or lutetium Lu 177 dotatate (Lutathera) beyond somatostatin analogs (SSAs).

Exclusion criteria included those with active brain metastases or cranial epidural disease, and those who had prior exposure to cabozantinib. Those with gastrointestinal (GI) bleeding or abnormalities determined to be clinically significant, tumor with invasion into the GI tract that could boost risk for GI bleeding or perforation, or those with tumor invading or encasing major blood vessels.

Study participants were randomized in a 2:1 fashion to receive 60 mg of oral cabozantinib once daily or placebo. Treatment continued until progressive disease or intolerable toxicity. Those in the pNET cohort were stratified based on whether they were concurrently receiving SSAs (yes vs no) or had prior exposure to sunitinib (yes vs no). Those in the epNET cohort were stratified based on current SSA use (yes vs no) and primary site (midgut GI/unknown vs non-midgut GI/lung/other).

The primary end point of the study was PFS by blinded independent radiology review committee and RECIST v1.1 criteria. Other key end points included ORR, DOR, and OS.

The median patient age in the pNET cohort was 60 years (range, 29-79); 57% of patients were male and the majority (83%) were White. Moreover, 27% of patients in this cohort received 1 prior systemic therapy, 26% had 2 prior therapies, and 46% had received 3 or more.

In the epNET cohort, the median patient age was 66 years (range, 28-86); 51% of patients were female and 84% were White. Primary tumor sites were small bowel (34%), which included duodenum, jejunum & ileum; lung (20%); thymus (5%); rectum (6%); cecum (2.0%); stomach (3.0%); non-cecum colon (1.0%); appendix (0.5%); others (18%); and unknown (12%). In this cohort, patients had previously received 1 (46%), 2 (29%), or 3 or more (25%) systemic therapies.

Safety Spotlight

The safety of cabozantinib was evaluated in 63 adult patients with unresectable, locally advanced or metastatic pNET enrolled in the trial. The median duration of treatment was 8.3 months (range, 0.1-37.8) with cabozantinib vs 2.9 months (range, 0.1-11.2) with placebo.

Serious adverse effects (AEs) were reported in 46% of patients. Moreover, dose interruptions or reductions were required for 83% and 49% of patients, respectively. Nineteen percent of patients experienced AEs that led to permanent treatment discontinuation.

The most common AEs reported in at least 20% of patients with pNET who received cabozantinib included fatigue, increased aspartate aminotransferase (AST) levels, increased alanine aminotransferase (ALT) levels, hypertension, diarrhea, rash, stomatitis, musculoskeletal pain, hyperglycemia, nausea, decreased platelet counts, dysgeusia, decreased neutrophil count, abdominal pain, decreased appetite, decreased hemoglobin, dizziness, hypophosphatemia hypothyroidism, vomiting, increased alkaline phosphatase (ALP), and decreased lymphocyte counts.

Safety of the agent was also evaluated in 132 patients with epNET. The median duration of treatment with cabozantinib was 5.4 months (range, 0.1-32.4) vs 2.9 months (range, 0.5-22.8) with placebo. Serious AEs were reported in 44% of these patients, with dose interruptions or reductions required by 81% and 38% of patients, respectively. Twenty-eight percent of patients permanently discontinued treatment with cabozantinib due to AEs.

In this cohort, the most common AEs experienced by at least 20% of patients who received cabozantinib were fatigue, increased AST levels, diarrhea, hypertension, increased ALT levels, decreased platelet counts, rash, stomatitis, nausea, decreased white blood cell counts, decreased neutrophil counts, musculoskeletal pain, dysgeusia, hypothyroidism, decreased appetite, decreased hemoglobin, hyperglycemia, abdominal pain, increased ALP, decreased lymphocyte counts, weight decreased, increased blood creatinine, hypoalbuminemia, blood bilirubin increased, hypocalcemia, hypokalemia, and hypomagnesemia.

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 26, 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. Cabozantinib. Prescribing information. Exelixis, Inc; March 2025. Accessed March 26, 2025.https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/208692s017lbl.pdf