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European Commission approves Ipsen’s Cabometyx™ (cabozantinib) Tablets for the treatment of advanced renal cell carcinoma (RCC) in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy
• Cabometyx™ (cabozantinib) is the first and only targeted therapy to improve Overall Survival (OS), Objective Response Rate (ORR), and Progression Free Survival (PFS) in RCC in METEOR randomized Phase 3 trial;
• Cabometyx™ (cabozantinib) improves OS across all evaluated patient subgroups;
• Cabometyx™ (cabozantinib) has a unique mechanism of action with the potential to overcome resistance to VEGFR tyrosine kinase inhibitors.
Ipsen, a global specialtydriven pharmaceutical group, today announced that the European Commission has approved Cabometyx™ (cabozantinib) 20, 40, 60 mg tablets for the treatment of advanced renal cell carcinoma (RCC) in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy. Cabometyx™ (cabozantinib) is the only single agent to demonstrate significant clinical benefits across all three efficacy endpoints (OS, PFS, ORR) in a phase 3 study in previously treated patients with RCC. This approval allows for the marketing of Cabometyx™ (cabozantinib) in previously treated advanced RCC in all 28 member states of the European Union, Norway and Iceland.
David Meek, Chief Executive Officer, Ipsen stated: “The approval of Cabometyx™ (cabozantinib) in Europe provides a breakthrough treatment to physicians and their patients suffering from renal cancer who failed on initial therapy. This oral drug has the potential to become a new standard of care in the second line setting of advanced renal cell carcinoma as it prolongs survival, slows disease progression, and shrinks tumors, with a clinically-acceptable safety and tolerability profile.”
Dr. Bernard Escudier, oncologist, kidney cancer and immunotherapy specialist at Institut Gustave Roussy, Villejuif (France) added: “The approval of Cabometyx™ (cabozantinib) by the European Commission brings a new treatment option offering survival benefit for patients with renal cancer who failed a prior treatment with a VEGFR-targeted therapy. This oral drug, in addition to targeting VEGF, has a unique mechanism of action targeting MET and AXL which are common pathways of resistance in renal cell carcinoma. Cabometyx™ also offers a convenient oral schedule for patients and flexibility of dosing for individualized treatment. ”
The approval is based on the results of a large, randomized phase 3 trial METEOR.
About CABOMETYX™ (cabozantinib)
Cabometyx™ (cabozantinib) targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the tyrosine kinase activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance.
On April 25, 2016, the U.S. Food and Drug Administration (FDA) approved Cabometyx™ (cabozantinib) for the treatment of patients with advanced RCC who have received prior antiangiogenic therapy.
On September 9, 2016, the European Commission approved Cabometyx™ (cabozantinib) for the treatment of advanced renal cell carcinoma in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy in the European Union, Norway and Iceland.
February 29, 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan.
About the METEOR Phase 3 Pivotal Trial
METEOR was an open-label, event-driven trial of 658 patients with advanced renal cell carcinoma who had failed at least one prior VEGFR TKI therapy. The primary endpoint was PFS in the first 375 patients randomized. Secondary endpoints included OS and objective response rate in all enrolled patients. The trial was conducted at approximately 200 sites in 26 countries, and enrollment was weighted toward Western Europe, North America, and Australia. Patients were randomized 1:1 to receive 60 mg of Cabometyx™ (cabozantinib) daily or 10 mg of everolimus daily and were stratified based on the number of prior VEGFR TKI therapies received and on MSKCC risk criteria. No cross-over was allowed between the study arms.
METEOR met its primary endpoint by significantly improving PFS. Compared with everolimus, Cabometyx™ (cabozantinib) was associated with a 42 percent reduction in the rate of disease progression or death. Median PFS for Cabometyx™ (cabozantinib) was 7.4 months versus 3.8 months for everolimus (HR=0.58, 95% CI 0.45-0.74, P<0.0001). Cabometyx™ (cabozantinib) also significantly improved the objective response rate compared with everolimus, be it through investigator assessment (24% versus 4%, p<0.0001) or through central review (17% versus 3%, p < 0.0001). These data were presented at the European Cancer Congress in September 2015 and published in The New England Journal of Medicine.1
Cabometyx™ (cabozantinib) also demonstrated a statistically significant and clinically meaningful increase in OS in the METEOR trial. Compared with everolimus, Cabometyx™ (cabozantinib) was associated with a 34 percent reduction in the rate of death. Median OS was 21.4 months for patients receiving Cabometyx™ (cabozantinib) versus 16.5 months for those receiving everolimus (HR=0.66, 95% CI 0.53-0.83, P=0.0003).
Cabometyx™ (cabozantinib) benefit in OS was robust and consistent across all pre-specified subgroups. In particular, benefit was observed regardless of risk category, location and extent of tumor metastases, and tumor MET expression level. These results were presented on June 5, 2016 at the ASCO Annual Meeting and concurrently published in The Lancet Oncology.2
At the time of the analysis, the median duration of treatment in the trial was 8.3 months with Cabometyx™ (cabozantinib) versus 4.4 months with everolimus. The most frequent adverse events regardless of causality were diarrhea, fatigue, decreased appetite and hypertension for Cabometyx™ and fatigue, anemia, decreased appetite and cough for everolimus. Dose reductions occurred for 62 percent and 25 percent of patients, respectively. Discontinuation rate due to an adverse event not related to disease progression was 12 percent with Cabometyx™ (cabozantinib) and 11 percent with everolimus.
About Advanced Renal Cell Carcinoma
Renal cell carcinoma (RCC) represents 2-3% of all cancers3, with the highest incidence occurring in Western countries. Generally, during the last two decades until recently, there has been an annual increase of about 2% in incidence both worldwide and in Europe, though in Denmark and Sweden a continuing decrease has been observed4. In 2012, there were approximately 84,400 new cases of RCC and 34,700 kidney cancer related deaths within the European Union5. In Europe, overall mortality rates for RCC have increased up until the early 1990s, with rates generally stabilizing or declining thereafter6. There has been a decrease in mortality since the 1980s in Scandinavian countries and since the early 1990s in France, Germany, Austria, the Netherlands, and Italy. However, in some European countries (Croatia, Estonia, Greece, Ireland, Slovakia), mortality rates still show an upward trend with increasing rates6.
The majority of clear cell RCC tumors have lower than normal levels of a protein called von HippelLindau, which leads to higher levels of MET, AXL and VEGF.7,8 These proteins promote tumor
angiogenesis (blood vessel growth), growth, invasiveness and metastasis.9-12 MET and AXL may provide escape pathways that drive resistance to VEGFR inhibitors.8,9
About Ipsen in oncology
Ipsen focuses its efforts in fighting cancers such as prostate cancer or those with high unmet medical needs such as bladder cancer, neuroendocrine tumors, kidney cancer and other niche oncology diseases. Our ambition is to offer new therapeutic options to patients and caregivers in their treatment journeys. Ipsen has a continuous commitment in innovative treatment development in oncology through an open innovation approach and using differentiated technological platforms notably in peptides. Moreover Ipsen has built scientific partnerships with trusted academic institutions, leading pharmaceutical and biotech companies and work with today’s top researchers and clinicians. We thus develop effective and innovative therapeutic solutions to improve treatment outcomes for patients and to support healthcare professionals in their daily practice.
About Ipsen
Ipsen (ipsen.com) is a global specialty-driven pharmaceutical group with total sales exceeding €1.4 billion in 2015. Ipsen sells more than 20 drugs in more than 115 countries, with a direct commercial presence in more than 30 countries. Ipsen’s ambition is to become a leader in specialty healthcare solutions for targeted debilitating diseases. Its fields of expertise cover oncology, neurosciences and endocrinology (adult & pediatric). Ipsen’s commitment to oncology is exemplified through its growing portfolio of key therapies improving the care of patients suffering from prostate cancer, bladder cancer and neuroendocrine tumors. Ipsen also has a significant presence in primary care. Moreover, the Group has an active policy of partnerships. Ipsen's R&D is focused on its innovative and differentiated technological platforms, peptides and toxins, located in the heart of the leading biotechnological and life sciences hubs (Les Ulis/Paris-Saclay, France; Slough/Oxford, UK; Cambridge, US). In 2015, R&D expenditure totaled close to €193 million. The Group has more than 4,600 employees worldwide. Ipsen’s shares are traded on segment A of Euronext Paris (stock code: IPN, ISIN code: FR0010259150) and eligible to the “Service de Règlement Différé” (“SRD”). The Group is part of the SBF 120 index. Ipsen has implemented a Sponsored Level I American Depositary Receipt (ADR) program, which trade on the over-the-counter market in the United States under the symbol IPSEY.
Ipsen Forward Looking Statement
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Financial Community: Eugenia Litz - Vice-President Investor Relations
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References
1. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015; 373(19):1814-1823.
2. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Onc. 2016 Jun 5; S1470-2045(16)30107-3.
3. European Network of Cancer Registries. Eurocim version 4.0. European incidence database V2.3, 730 entity dictionary (2001), Lyon, 2001.
4. Lindblad P. Epidemiology of renal cell carcinoma. Scand J Surg 2004;93(2):88-96 ncbi.nlm.nih.gov/pubmed/15285559
5. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 2013 Apr;49(6):1374-403. ncbi.nlm.nih.gov/pubmed/23485231
6. Levi F, Ferlay J, Galeone C, et al. The changing pattern of kidney cancer incidence and mortality in Europe. BJU Int 2008 Apr;101(8):949-58 ncbi.nlm.nih.gov/pubmed/18241251
7. Harshman, L.C. and Choueiri, T.K., Targeting the hepatocyte growth factor/c-Met signaling pathway in renal cell carcinoma. Cancer J. 2013; 19(4):316-323.
8. Rankin et al., Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci U S A. 2014; 111(37):13373-13378.
9. Zhou L, Liu X-D, Sun M, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2015 Sep 14. doi:10.1038/onc.2015.343. [Epub ahead of print].
10. Koochekpour et al., The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells. Mol Cell Biol. 1999; 19(9):5902 5912.
11. Takahashi A, Sasaki H, Kim SJ, et al. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res. 1994;54:4233-4237.
12. Nakagawa M, Emoto A, Hanada T, Nasu N, Nomura Y. Tubulogenesis by microvascular endothelial cells is mediated by vascular endothelial growth factor (VEGF) in renal cell carcinoma. Br J Urol. 1997;79:681-687.
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