Cabozantinib Wins EU Approval for Previously Treated Advanced Pancreatic and Extra-Pancreatic Neuroendocrine Tumors

The European Commission (EC) has approved cabozantinib (Cabometyx) for adult patients with unresectable or metastatic, well-differentiated pancreatic (pNET) and extra-pancreatic (epNET) neuroendocrine tumors (NETs) who have progressed following at least 1 prior systemic therapy other than somatostatin analogues.¹

This regulatory decision makes cabozantinib the first and only systemic therapy to be approved in the European Union for previously treated unresectable or metastatic NETs, regardless of tumor site, grade, or previous non–somatostatin analogue–based systemic therapy.

Findings from the pivotal phase 3 CABINET trial (NCT03375320)​​ supported the agent’s approval.

Final results presented at the 2024 ESMO Congress and subsequently published in the New England Journal of Medicine demonstrated a 77% and 62% reduction in the risk of disease progression or death with cabozantinib vs placebo in the pNET (n = 95) and epNET (n = 203) cohorts, respectively.^1,2

In the epNET cohort, the median progression-free survival (PFS) was 8.4 months (95% CI, 7.6-12.7) vs 3.9 months (95% CI, 3.0-5.7) with cabozantinib and placebo, respectively (HR, 0.38; 95% CI, 0.25-0.59; P < .001).² The median PFS in the pNET cohort was 13.8 months (95% CI, 9.2-18.5) vs 4.4 months (95% CI, 3.0-5.9) with cabozantinib and placebo, respectively (HR, 0.23; 95% CI, 0.12-0.42; P < .001).

The confirmed objective response rate (ORR) with cabozantinib in the epNET and pNET cohorts, respectively, was 5% and 19%; comparably, the ORR was 0% in those treated with placebo. Notably, overall survival (OS) data were not mature at the time of the analysis and were potentially confounded by the trial’s crossover design.¹

“The complex nature of NETs and lack of innovation in recent years has resulted in significant physical and emotional strain for patients as their disease progresses,” Sandra Silvestri, MD, PhD, executive vice president and chief medical officer of Ipsen, stated in a news release. “We are pleased that for the first time, this approval offers a unique, simplified, and efficacious treatment option upon progression, where few to no other options currently exist. We look forward to working with local health authorities to make cabozantinib available to even more patients, reinforcing our longstanding commitment to delivering transformational therapies in oncology.”

Notably, data from CABINET also supported the March 2025 FDA approval of cabozantinib for the treatment of adult and pediatric patients 12 years of age or older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pNETs and epNETs.³

Inside the CABINET Trial: Study Overview

CABINET was a multicenter, randomized, double-blinded, placebo-controlled study evaluating the efficacy and safety of cabozantinib compared with placebo in 2 cohorts of patients with unresectable, locally advanced or metastatic pNET or epNET who had progressed on previous therapy.⁴

Eligible patients had well- or moderately-differentiated pNET or non-pancreatic NET (carcinoid) pathology, locally advanced/unresectable or metastatic disease; histologic documentation of NETs located in pancreatic, gastrointestinal, lung, thymus, other, or unknown primary site; and radiographic evidence of disease progression within 12 months prior to enrollment, per RECIST 1.1 criteria. All patients were required to have measurable disease by CT or MRI and have progressed on prior treatment.

Key exclusion criteria included active brain metastases, cranial epidural disease, prior treatment with cabozantinib, and clinical features increasing the risk of gastrointestinal bleeding or perforation.

At the time of the final analysis, a total of 298 patients in the United States were enrolled onto the study and were randomly assigned 2:1 to receive oral cabozantinib at 60 mg once daily or placebo. Randomization and statistical analysis were conducted independently for each histologic cohort. The trial was stopped early following an interim analysis demonstrating a statistically significant improvement in PFS with cabozantinib vs placebo in both cohorts.

The study’s primary end point was PFS as assessed by blinded independent central review.^1,4 Secondary end points included ORR, OS, and safety.

Additional Safety and QOL Data

Safety data for cabozantinib in both cohorts were consistent with the agent’s known toxicity profile, and no new safety signals were identified.¹ The incidence of grade 3 or higher adverse effects (AEs) was 62% to 65% among patients treated with cabozantinib vs 23% to 27% with placebo.³ The most common grade 3 or higher treatment-related AEs were hypertension, fatigue, diarrhea, and thromboembolic events.

Health-related quality-of-life outcomes were also found to be maintained or improved with cabozantinib vs placebo per findings from an analysis presented at the 2025 ASCO Annual Meeting.¹

“Sequential use of systemic therapies remains challenging in the different types of NETs that may arise from various organ sites,” Marianne Pavel, MD, endocrinologist and NET expert in the Department of Medicine at Friedrich-Alexander University of Erlangen, Germany, concluded in the news release. “The number of available therapies is limited, and not all [patients with] NET may benefit from currently approved therapies. Advancements like those achieved through the CABINET study, as recognized by the approval for cabozantinib n a wide range of NET, is offering new treatment opportunities to delay disease progression in patients with well-differentiated NET, irrespective of the type of NET.”

References

1. Cabometyx approved in the EU for previously treated advanced neuroendocrine tumors. Ipsen. July 24, 2025. Accessed July 24, 2025. https://ml-eu.globenewswire.com/Resource/Download/1f6cb083-99c6-45eb-95ff-fa79a990f6f4
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. FDA. March 26, 2025. Accessed July 24, 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
4. Testing cabozantinib in patients with advanced pancreatic neuroendocrine and carcinoid tumors. ClinicalTrials.gov. Updated June 12, 2025. Accessed July 24, 2025. https://clinicaltrials.gov/study/NCT03375320