CHMP Issues a Positive Opinion for Cabozantinib in Previously Treated Advanced Neuroendocrine Tumors

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion for cabozantinib (Cabometyx®*; Ipsen Pharma)** for adult patients with unresectable or metastatic, well differentiated extra-pancreatic (epNET) and pancreatic (pNET) neuroendocrine tumors who have progressed following at least one prior systemic therapy other than somatostatin analogues.

A final decision on the approval in the European Union is expected in the coming months. However, if approved, cabozantinib would be the first and only systemic therapy approved in the European Union for previously treated neuroendocrine tumors, regardless of tumor site, grade or previous non-somatostatin analogue-based systemic therapy [1][2]

CABINET-trial
This CHMP-recommendation is based on results from the CABINET Phase 3 trial (–(CABozantinib versus placebo In patients with advanced NEuroendocrine Tumors after progression on prior therapy; NCT03375320), presented at the European Society of Medical Oncology (ESMO) Congress 2024 and published in the New England Journal of Medicine. [3][4] A final decision on the approval in the European Union is expected in the coming months.

The study was funded, in part, by the National Cancer Institute (NCI), part of the National Institutes of Health in the U.S., and is being led and conducted by the NCI-funded Alliance for Clinical Trials in Oncology.

Increase
The number of people newly diagnosed with neuroendocrine tumors (NETs) is believed to be increasing, with a higher estimated prevalence than pancreatic or bladder cancer. [5][6][7]

Most forms of NETs develop slowly and can originate in various parts of the body, [8] often requiring multiple lines of therapy as the disease progresses.[1][2] Treatment options upon progression are often limited depending on primary tumor site and other factors, making it challenging to define optimal sequencing of treatments specific to individual patient needs.[1][2][9] In particular, for the 27% of people diagnosed with lung NETs,[10] there are no approved treatment options available upon progression on a non-somatostatin analogue-based systemic therapy.[1][2]

“The significant efficacy data demonstrated in the CABINET Phase 3 trial have provided the opportunity to reframe conversations on care approaches for people living with advanced pancreatic and extra-pancreatic neuroendocrine tumors,” noted Christelle Huguet, PhD, EVP and Head of Research and Development, Ipsen.

“Today’s positive CHMP opinion confirms the potential to translate these data into meaningful benefits for patients and we look forward to receiving the final decision from the European Commission,” Huguet added.

Five-year survival
The five-year survival rate is highly dependent on the primary site of disease. For advanced gastrointestinal and lung NETs, where the cancer has spread to distant parts of the body, the five-year survival rates are 68% and 55%, respectively.[11][12] For people diagnosed with advanced pNET, however, the prognosis is poor, with a five-year survival rate of 23%.[13]

The positive CHMP opinion is based on data from the CABINET Phase 3 trial, which investigated cabozantinib versus placebo in people living with advanced pNETs or epNETs, whose disease had progressed after prior systemic therapy other than somatostatin analogues.[3][4]

• In the pNET cohort, at a median follow-up of 13.8 months, median PFS was 13.8 months for cabozantinib versus 4.4 months for placebo (hazard ratio (HR) 0.23 [95% confidence interval (CI) 0.12-0.42] p<0.001).[3][4]
• In the epNET cohort, at a median follow-up of 10.2 months, median PFS based on local radiology review was 8.4 months for cabozantinib versus 3.9 months for placebo (HR 0.38 [95% CI 0.25-0.59] p<0.001).[3][4]
• Overall survival data were not mature at the time of the analyses and potentially confounded by the crossover design of the CABINET trial.[3][4]
• The safety profile of cabozantinib observed in each cohort was consistent with its known safety profile; no new safety signals were identified.[3][4]
• A presentation at the 2025 annual meeting of American Society of Clinical Oncology (ASCO), showed that health-related quality of life was also found to be maintained or improved.[14]

__

Note: * Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases, including VEGFRs, MET, RET and the TAM family (TYRO3, MER, AXL).[15] These receptor tyrosine kinases are involved in both normal cellular function and pathological processes such as oncogenesis, metastasis, tumor angiogenesis (the growth of new blood vessels that tumors need to grow), drug resistance, immune modulation, and maintenance of the tumor microenvironment.[15][16][17][18]
** In 2016, Exelixis granted Ipsen Pharma SAS exclusive rights for the commercialization and further clinical development of cabozantinib outside of the U.S. and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the U.S.

Clinical trials
Testing Cabozantinib in Patients With Advanced Pancreatic Neuroendocrine and Carcinoid Tumors – ClinicalTrials.gov ID NCT03375320

Highlights of prescribing information
Cabozantinib (Cabometyx®; Exelixis) [Prescribing information]

Summary of Product Characteristics (SPC) [16]
Cabozantinib (Cabometyx®; Ipsen Pharma) [Product Characteristics]

References
[1] Baudin E, Caplin M, Garcia-Carbonero R, Fazio N, Ferolla P, Filosso PL, Frilling A, de Herder WW, Hörsch D, Knigge U, Korse CM, Lim E, Lombard-Bohas C, Pavel M, Scoazec JY, Sundin A, Berruti A; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Corrigendum to “Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up”: [Annals of Oncology 32 (2021) 439-451]. Ann Oncol. 2021 Nov;32(11):1453-1455. doi: 10.1016/j.annonc.2021.08.2150. Epub 2021 Sep 29. Erratum for: Ann Oncol. 2021 Apr;32(4):439-451. doi: 10.1016/j.annonc.2021.01.003. PMID: 34598840.
[2] Pavel M, Öberg K, Falconi M, Krenning EP, Sundin A, Perren A, Berruti A; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020 Jul;31(7):844-860. doi: 10.1016/j.annonc.2020.03.304. Epub 2020 Apr 6. PMID: 32272208.
[3] Chan JA, Geyer S, Zemla T, Knopp MV, Behr S, Pulsipher S, Ou FS, Dueck AC, Acoba J, Shergill A, Wolin EM, Halfdanarson TR, Konda B, Trikalinos NA, Tawfik B, Raj N, Shaheen S, Vijayvergia N, Dasari A, Strosberg JR, Kohn EC, Kulke MH, O’Reilly EM, Meyerhardt JA. Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors. N Engl J Med. 2025 Feb 13;392(7):653-665. doi: 10.1056/NEJMoa2403991. Epub 2024 Sep 16. PMID: 39282913; PMCID: PMC11821447.
[4] Chan et al. Cabozantinib Versus Placebo for Advanced Neuroendocrine Tumors (NET) after Progression on Prior Therapy (CABINET Trial/Alliance A021602): Updated Results Including Progression Free-Survival (PFS) by Blinded Independent Central Review (BICR) and Subgroup Analyses. As presented at ESMO Congress 2024 during the ‘Proffered Paper: NETs and Endocrine Tumors at 2:45 p.m. CEST Barcelona, Spain.
[5] Durma AD, Saracyn M, Kołodziej M, Jóźwik-Plebanek K, Dmochowska B, Kapusta W, Żmudzki W, Mróz A, Kos-Kudła B, Kamiński G. Epidemiology of Neuroendocrine Neoplasms and Results of Their Treatment with [¹⁷⁷Lu]Lu-DOTA-TATE or [¹⁷⁷Lu]Lu-DOTA-TATE and [⁹⁰Y]Y-DOTA-TATE-A Six-Year Experience in High-Reference Polish Neuroendocrine Neoplasm Center. Cancers (Basel). 2023 Nov 18;15(22):5466. doi: 10.3390/cancers15225466. PMID: 38001726; PMCID: PMC10670106.
[6] Singh S, Granberg D, Wolin E, Warner R, Sissons M, Kolarova T, Goldstein G, Pavel M, Öberg K, Leyden J. Patient-Reported Burden of a Neuroendocrine Tumor (NET) Diagnosis: Results From the First Global Survey of Patients With NETs. J Glob Oncol. 2016 Jun 8;3(1):43-53. doi: 10.1200/JGO.2015.002980. PMID: 28717741; PMCID: PMC5493232.[7] Globocan: International Agency for Research on Cancer – Cancer Today. Online. Last accessed in June 2025
[8] Neuroendocrine tumor (NET). National Cancer institute. Online.  Last accessed in June 2025.
[9] McClellan, K., Chen. E.Y, Kardosh A., et al. Therapy Resistant Gastroenteropancreatic Neuroendocrine Tumors.Cancers. 2022, 14(19), 4769.
[10] Frilling A, Akerström G, Falconi M, Pavel M, Ramos J, Kidd M, Modlin IM. Neuroendocrine tumor disease: an evolving landscape. Endocr Relat Cancer. 2012 Sep 14;19(5):R163-85. doi: 10.1530/ERC-12-0024. PMID: 22645227.
[11] Survival Rates for Gastrointestinal Carcinoid Tumors. American Cancer Society. Online. Last accesses in June 2025
[12] Survival Rates for Lung Carcinoid Tumors. American Cancer Society. Online. Last accessed in June 2025
[13] Survival Rates for Pancreatic Neuroendocrine Tumor. American Cancer Society. Online. Last accessed in June 2025.
[14] Duech et al. Health-related quality of life (HRQOL) in the phase 3 trial of cabozantinib vs placebo for advanced neuroendocrine tumors (NET) after progression on prior therapy (CABINET, Alliance A021602). As presented at ASCO Congress 2025. https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.4020 [Abstract]
[15] El-Khoueiry AB, Hanna DL, Llovet J, Kelley RK. Cabozantinib: An evolving therapy for hepatocellular carcinoma. Cancer Treat Rev. 2021 Jul;98:102221. doi: 10.1016/j.ctrv.2021.102221. Epub 2021 May 12. PMID: 34029957.
[16] European Medicines Agency. Cabometyx® (cabozantinib) EU Summary of Product Characteristics. Online. Last accesses in June 2025
[17] Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou YC, Joly AH. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011 Dec;10(12):2298-308. doi: 10.1158/1535-7163.MCT-11-0264. Epub 2011 Sep 16. PMID: 21926191.
[18] Hsu CH, Huang YH, Lin SM, Hsu C. AXL and MET in Hepatocellular Carcinoma: A Systematic Literature Review. Liver Cancer. 2022 Feb 10;11(2):94-112. doi: 10.1159/000520501. PMID: 35634427; PMCID: PMC9109073.

Featured image: European Medicine Agency. Photo courtesy © 2018 – 2025 Sunvalley Communication. Used with permission

DOI