Cabozantinib Bests Placebo in Extrapancreatic NETs With Primary Tumor Arising in the Gl Tract

Cabozantinib (Cabometyx) improved progression-free survival (PFS) vs placebo after progression on prior therapy in patients with extrapancreatic neuroendocrine tumors (NETs) with a primary tumor arising in the gastrointestinal (Gl) tract, according to subgroup data from the phase 3 CABINET trial (NCT03375320) presented at the 2025 Gastrointestinal Cancers Symposium.1 The VEGF-targeted agent also improved PFS vs placebo in patients with various clinical factors, except in those with a primary site of a non-midgut GI tumor.

Findings from the analysis revealed that patients in the extrapancreatic NET cohort with a primary tumor arising in the Gl tract (n = 116) experienced a median PFS of 8.5 months (95% CI, 6.0-16.7) in the cabozantinib arm (n = 70) vs 5.6 months (95% CI, 3.9-11.0) in the placebo arm (n = 46; stratified HR, 0.50; 95% CI, 0.28-0.88; 1-sided stratified log-rank P = .007). Best overall responses in the cabozantinib and placebo arms included confirmed partial response (1% vs 0%), stable disease (69% vs 65%), and progressive disease (9% vs 26%), and patients were also not evaluable (21% vs 9%), respectively.

“New therapeutic options are needed for patients with advanced NETs,” Jonathan Strosberg, MD, leader of the Neuroendocrine Tumor Division and Department of Gastrointestinal Oncology Research Program at Moffitt Cancer Center in Tampa, Florida, wrote in a poster presentation of the findings. “Potential benefit was observed across clinical factors including grade, functional status, [use] concurrent somatostatin analogs, and prior treatment.”

Prior data from CABINET showed that cabozantinib significantly improved PFS vs placebo in patients with previously treated, progressive advanced extrapancreatic (stratified HR, 0.38; 95% CI, 0.25-0.59; P < .001) or pancreatic NETs (stratified HR, 0.23; 95% CI, 0.12-0.42; P < .001).2 Confirmed objective response rates were 5% and 19% in patients with extrapancreatic and pancreatic NETs, respectively.

Patients enrolled in CABINET had grade I to III well to moderately differentiated NETs and had experienced disease progression within 12 months prior to random assignment following treatment with at least 1 prior FDA-approved systemic therapy, not including somatostatin analogs.1 They were then assigned to the extrapancreatic NET arm or pancreatic NET arm and randomly assigned 2:1 to receive 60 mg of cabozantinib or placebo. The primary end point of the trial was PFS.

Baseline Patient Characteristics From the Subgroup Analysis

Findings from the present analysis showed that patients with extrapancreatic NETs with a primary tumor arising in the Gl tract were a median age of 66 years (range, 28-86) in the cabozantinib arm and 67 years (range, 42-78) in the placebo arm. Patients in the cabozantinib and placebo arms were female (49% vs 41%, respectively), had an ECOG performance score of 1 (60% vs 50%), had a functional tumor (47% vs 44%), and received concurrent somatostatin analogs (87% vs 80%). Furthermore, patients had grades I (40% vs 28%), II (54% vs 61%), and III (4% vs 9%) disease and this status was unknown for 1% vs 2% of patients, respectively. Additionally, primary tumor sites included jejunum/ileum/cecum/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/biliary (1% vs 9%), respectively.

The median number of prior systemic therapies received, not including somatostatin analogs, was 1 in both the cabozantinib (range, 1-6) and placebo (range, 1-5) arms. All patients had received somatostatin analogs previously, and most had received everolimus (Afinitor; 61% vs 54%) or lutetium Lu 177 dotatate (Lutathera; 79% vs 74%), and some were given temozolomide (Temodar)–based therapies (17% vs 15%).

The median duration of therapy was 5.8 months (range, 0.6-32.4) among patients treated with cabozantinib (n = 68) with an average daily dose of 38.9 mg given and the median duration of therapy was 3.7 months (range, 0.6-21.4) among those given placebo (n = 45) with an average daily dose of 59.3 mg. Additionally, 13 vs 7 patients remained on treatment in the respective arms as of the unblinding data cutoff date of August 24, 2023. Reasons for discontinuation of blinded treatment included progressive disease (n = 24; n = 23), adverse effects (AEs; n = 16; n = 5), withdrawn consent (n = 6; n = 4), and death on study (n = 4; n = 0).

Additional Findings and Safety

Cabozantinib yielded a PFS benefit vs placebo among all clinical factor groups examined in this subgroup analysis aside from in those with a primary tumor site of non-midgut GI (HR, 2.38; 95% CI, 0.69-8.15). The most pronounced benefit was seen in those who had not received prior lutetium Lu 177 dotatate (HR, 0.19; 95% CI, 0.05-0.71), had grade I disease (HR, 0.30; 95% CI, 0.13-0.68), had an ECOG performance 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).

The safety profile of cabozantinib was consistent with previously reported data, and in this patient population treated with the agent (n = 68) vs placebo (n = 45), grade 3 to 4 AEs occurred in 60% vs 18% of patients. Notable grade 3 to 4 AEs included hypertension (19% vs 4%), diarrhea (13% vs 4%), and fatigue (10% vs 4%), respectively. Grade 5 toxicities that may have been related to study treatment occurred in 3 patients treated with cabozantinib; 1 patient experienced cardiac arrest, and the other 2 causes of death were not specified.

References

1. 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
2. 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