Cabozantinib (s)-Malate

PARIS, France I July 24, 2025 I Ipsen announced today that the European Commission has approved Cabometyx ® (cabozantinib) for adult patients with unresectable or metastatic, well differentiated pancreatic (pNET) and extra-pancreatic (epNET) neuroendocrine tumors who have progressed following at least one prior systemic therapy other than somatostatin analogues. Most forms of neuroendocrine tumors (NETs) develop slowly, can originate in various parts of the body 5 and require 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. 1,2,6 In particular, for the 27% of people diagnosed with lung NETs 7 , there have been no approved treatment options upon progression on a prior therapy. 1,2 “The complex nature of neuroendocrine tumors and lack of innovation in recent years has resulted in significant physical and emotional strain for patients as their disease progresses,” said Sandra Silvestri, MD, PhD, EVP and Chief Medical Officer, Ipsen. “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 Cabometyx ® available to even more patients, reinforcing our longstanding commitment to delivering transformational therapies in oncology.” NETs can have a significant impact on both individuals’ lives and wider society, with 71% of people reporting NETs having a negative effect on their daily life, with 92% reporting that they have to make lifestyle changes to accommodate their disease. 8 “Sequential use of systemic therapies remains challenging in the different types of neuroendocrine tumor (NET) that may arise from various organ sites. The number of available therapies is limited and not all NET patients may benefit from currently approved therapies,” said Professor Marianne Pavel, Endocrinologist and NET expert at the Department of Medicine 1, Friedrich-Alexander University of Erlangen, Germany. “Advancements like those achieved through the CABINET Phase III study, as recognized by the approval for Cabometyx in 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 neuroendocrine tumor.” The EC approval was based on data from the CABINET Phase III trial which investigated Cabometyx versus placebo in people living with advanced pNETs or epNETs whose disease had progressed after prior systemic therapy. Final results from the trial, as presented at the 2024 European Society for Medical Oncology Congress and simultaneously published in the New England Journal of Medicine , demonstrated progression-free survival (PFS) benefits in favor of Cabometyx versus placebo: 3,4 About Cabometyx Cabometyx is a small molecule that inhibits multiple receptor tyrosine kinases, including VEGFRs, MET, RET and the TAM family (TYRO3, MER, AXL). 10 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. 10,11,12,13 Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of Cabometyx outside of the U.S. and Japan. Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited (Takeda) for the commercialization and further clinical development of Cabometyx for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize Cabometyx in the U.S. In over 65 countries outside of the United States and Japan, including in the European Union, Cabometyx is currently indicated as: 11 About CABINET (Alliance A021602) CABINET (randomized, double-blinded Phase III trial of CABozantinib versus placebo In patients with advanced Neuroendocrine Tumors after progression on prior therapy) is sponsored 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 with participation from the NCI-funded National Clinical Trials Network, as part of Exelixis’ collaboration through a Cooperative Research and Development Agreement with the NCI’s Cancer Therapy Evaluation Program. The multicenter Phase III CABINET pivotal trial enrolled a total of 298 patients in the U.S. at the time of the analysis. Patients were randomized 2:1 to Cabometyx or placebo in two separately powered cohorts. The epNET cohort included patients with the following primary tumor sites: gastrointestinal tract, lung, unknown primary and other organs. Each cohort was randomized separately and had its own statistical analysis plan. Patients must have had measurable disease per RECIST 1.1 criteria and must have experienced disease progression or intolerance after at least one U.S. Food and Drug Administration-approved line of prior systemic therapy other than somatostatin analogues. The primary endpoint in each cohort was PFS per RECIST 1.1 by retrospective blinded independent central review. Upon confirmation of disease progression, patients were unblinded, and those receiving placebo were permitted to cross over to open-label therapy with Cabometyx. Secondary endpoints included overall survival, objective response rate and safety. More information about this trial is available at ClinicalTrials.gov . About Ipsen We are a global biopharmaceutical company with a focus on bringing transformative medicines to patients in three therapeutic areas: Oncology, Rare Disease and Neuroscience. Our pipeline is fueled by external innovation and supported by nearly 100 years of development experience and global hubs in the U.S., France and the U.K. Our teams in more than 40 countries and our partnerships around the world enable us to bring medicines to patients in more than 100 countries. Ipsen is listed in Paris (Euronext: IPN) and in the U.S. through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information, visit ipsen.com. References 1 Pavel M, et al . Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(7):844-860. 2 Baudin E, et al. Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021 Nov;32(11):1453-1455. 3 Chan et al. Phase 3 Trial of Cabozantinib in Previously Treated Advanced Neuroendocrine Tumors. 2024 New England Journal of Medicine. DOI: 10.1056/NEJMoa2403991 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 Neuroendocrine tumor (NET). https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-endocrine-tumor/carcinoid-tumor. Accessed July 2025. 6 McClellan, K., Chen. E.Y, Kardosh A., et al. Therapy Resistant Gastroenteropancreatic Neuroendocrine Tumors. Cancers. 2022, 14(19), 4769. 7 Frilling et al. Neuroendocrine tumor disease: an evolving landscape. 2012. 19:R163-R185 8 Singh et al. Patient-Reported Burden of a Neuroendocrine Tumor (NET) Diagnosis: Results From the First Global Survey of Patients With NETs. J Glob Oncol. 2017 Feb; 3(1): 43–53. 9 Dueck 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. 10 El-Khoueiry A. et al., Cabozantinib: An evolving therapy for hepatocellular carcinoma. Cancer Treatment Reviews. 2021 Jul;98:102221. DOI: 10.1016/j.ctrv.2021.102221. 11 European Medicines Agency. Cabometyx® (cabozantinib) EU Summary of Product Characteristics. Available from: https://www.ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf . Accessed July 2025. 12 Yakes M. et al ., Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10:2298–2308. DOI: 10.1158/1535-7163.MCT-11-0264 13 Hsu et al., AXL and MET in Hepatocellular Carcinoma: A Systematic Literature Review. Liver Cancer 2021 DOI: 10.1159/000520501 SOURCE: Ipsen

The European Commission authorised a broader label for Ipsen’s tyrosine kinase inhibitor (TKI) Cabometyx (cabozantinib), to include neuroendocrine tumours (NET).Specifically, the approval applies to adults with unresectable, locally advanced or metastatic, well-differentiated pancreatic NET (pNET) or extra-pancreatic NET (epNET), who have previously received at least one systemic therapy, except a somatostatin analogue.“The availability of Cabometyx in the [EU]…is a significant milestone as there have been limited treatment advancements in the past decade, including very few options shown to improve outcomes across a heterogeneous population,” said Amy Peterson, chief medical officer of Exelixis. The label expansion follows a similar FDA approval in adults and children aged 12 and older earlier this year and succeeds a favourable recommendation by the EMA’s drug advisory panel last month. The latest EU clearance was backed by the Phase III CABINET trial — involving 203 patients with epNET, and 95 with pNET — which was stopped early owing to an “unprecedented” efficacy benefit at the interim analysis. Full results unveiled at last year’s European Society for Medical Oncology (ESMO) meeting showed that the TKI cut the risk of disease progression by 62% in the epNET cohort, and by 77% in the pNET cohort versus placebo. Ipsen, which holds rights to Cabometyx outside the US and Japan, has previously secured EU approvals for the drug in advanced renal cell carcinoma, hepatocellular carcinoma and locally advanced or metastatic differentiated thyroid carcinoma. Meanwhile, Exelixis markets the TKI in the US and Takeda does so in Japan.