Cabozantinib Benefit Holds in Advanced NETs, Regardless of Hormone Functional Status

Cabozantinib (Cabometyx) improved progression-free survival (PFS) compared with placebo in patients with advanced neuroendocrine tumors (NETs) whether or not their tumors secreted hormones, with a safety profile consistent with the overall trial population, according to a post hoc subgroup analysis of the phase 3 CABINET trial (NCT03375320) presented by Nikolaos A. Trikalinos, MD, MS, Washington University in St Louis and Siteman Cancer Center, at the 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium.

PFS Benefit in Both Functional and Nonfunctional NETs

The analysis included 74 patients with functional NETs (47 received cabozantinib and 27 received placebo) and 179 patients with nonfunctional NETs (123 received cabozantinib and 56 received placebo).

Cabozantinib prolonged PFS compared with placebo regardless of functional status. In patients with functional NETs, median PFS was 12.7 months with cabozantinib vs 5.4 months with placebo (HR, 0.40; 95% CI, 0.20-0.82; P = .012). In patients with nonfunctional NETs, median PFS was 9.4 months vs 3.1 months, respectively (HR, 0.26; 95% CI, 0.17-0.41; P < .001).

Because functional and nonfunctional tumors differed in grade, primary site, and other features, the investigators also performed analyses adjusted for tumor grade and ECOG performance status at baseline. Trikalinos noted that such an analysis was a common request when earlier results from this subgroup work were shared. The benefit held after adjustment, with an HR of 0.38 (95% CI, 0.18-0.78; P = .0085) in functional tumors and 0.24 (95% CI, 0.15-0.37; P < .0001) in nonfunctional tumors.

These findings are consistent with the PFS benefit seen across the full CABINET population.

Cabozantinib Safety Was Similar Across Groups

The most common adverse events (AEs) with cabozantinib were fatigue, hypertension, diarrhea, and elevations in liver enzymes, and these occurred at broadly similar rates in patients with functional and nonfunctional tumors. Hypertension was the most frequent grade 3 or higher AE in both groups, affecting about one-fifth of patients receiving cabozantinib.

Diarrhea was a particular concern given that patients with functional tumors, especially those with carcinoid syndrome, may already experience hormone-related diarrhea and fatigue. However, rates of any-grade and grade 3 or higher diarrhea with cabozantinib were comparable between subgroups, and grade 3 or higher fatigue was in fact less common among patients with functional tumors.

“There really [hasn’t] been that much difference between functional and non-functional tumors,” Trikalinos said of the safety findings.

Why Functional Status Matters

In the primary CABINET analysis, cabozantinib significantly prolonged PFS vs placebo in patients with previously treated, advanced extra-pancreatic NETs (epNETs) and pancreatic NETs (pNETs).² Those results supported the March 2025 FDA approval of cabozantinib for adult and pediatric patients 12 years and older with previously treated, well-differentiated pNETs and epNETs.³

The trial enrolled patients with both functional NETs, which cause symptoms through hormone secretion, and nonfunctional NETs. Because these groups can follow different clinical courses and are often managed differently, investigators set out to determine whether the efficacy and tolerability of cabozantinib varied by hormone functional status.

“These patients have different trajectories, different treatments,” Trikalinos said, adding that a key concern was whether the side effects of cabozantinib might add to the symptom burden that patients with functional tumors already carry.

CABINET Trial Design and Patient Characteristics

CABINET (Alliance A021602) was a randomized, double-blind, placebo-controlled phase 3 study with 2 independent cohorts: 203 patients with epNETs and 95 patients with pNETs. In each cohort, patients were randomly assigned 2:1 to cabozantinib 60 mg daily or placebo. After disease progression was confirmed by central radiology review, patients could be unblinded, and those receiving placebo could cross over to open-label cabozantinib.

Eligible patients had well- to moderately differentiated grade 1 to 3 NETs with disease progression by RECIST within 12 months before randomization. Patients also needed progression on, or intolerance to, at least 1 prior FDA-approved systemic therapy other than somatostatin analogues (SSAs), such as everolimus, sunitinib, or lutetium Lu 177 dotatate, depending on tumor site. Concurrent SSA therapy was allowed if the dose had been stable for at least 2 months.

The primary end point in each cohort was PFS by blinded independent central review. Secondary end points included overall survival, objective response rate, and safety and tolerability. For this subgroup analysis, 45 patients with unknown functional status were excluded.

The functional and nonfunctional groups differed in several important ways. Functional tumors most often arose in the gastrointestinal (GI) tract, while nonfunctional tumors more often originated in the pancreas and lung. Concurrent SSA use was also far more common in patients with functional tumors, at roughly 90% compared with about half of patients with nonfunctional tumors. Trikalinos noted that how continued SSA therapy might influence outcomes is not well understood.

Hormone production patterns varied by site of origin. Serotonin was the predominant hormone among functional GI and lung NETs, consistent with carcinoid syndrome. Functional pNETs produced a broader mix of hormones, including gastrin, glucagon, insulin, somatostatin, and vasoactive intestinal peptide, while 1 thymic tumor secreted adrenocorticotropic hormone.

Clinical Implications and Next Steps

Taken together, the investigators concluded that cabozantinib is an effective treatment option for patients with either functional or nonfunctional NETs, and that efficacy and safety in both subgroups are consistent with results for the overall trial.

Several questions remain. Whether cabozantinib has a direct effect on hormone secretion and symptom control in functional tumors has not yet been established. Analyses of biochemical response, including changes in tumor markers such as 5-hydroxyindoleacetic acid, are ongoing but are limited by the small number of patients in some hormone subgroups.

Still, the data offer reassurance to clinicians weighing cabozantinib for patients whose disease is complicated by hormone-related symptoms, a population for whom concerns about overlapping toxicities such as diarrhea and fatigue might otherwise give pause.

REFERENCES

1. Trikalinos NA, Geyer S, Zemla T, et al. Efficacy and safety of cabozantinib in advanced neuroendocrine tumors according to hormone functional status: subgroup analysis of the phase 3 CABINET trial (Alliance A021602). Presented at: 2026 NANETS Multidisciplinary NET Medical Symposium; November 5-7, 2026; Las Vegas, NV.

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. FDA approves cabozantinib for adults and pediatric patients 12 years of age and older with pNET and epNET. US Food and Drug Administration. March 26, 2025. Accessed November 6, 2026. https://tinyurl.com/mr52xap9