European Commission approves Ipsen’s Cabometyx® (cabozantinib) for the first-line treatment of adults with intermediate- or poor- risk advanced renal cell carcinoma 

Ipsen (Euronext: IPN; ADR: IPSEY) today announced that the European Commission (EC) has approved Cabometyx® (cabozantinib) 20, 40, 60 mg for the first-line treatment of adults with intermediate- or poor- risk advanced renal cell carcinoma (aRCC). This approval allows for the marketing of Cabometyx® (cabozantinib) in this indication in all 28 member states of the European Union, Norway and Iceland.
“Today’s EC approval is a step forward for advanced kidney cancer patients in Europe who will be able to access a new oral first-line treatment option that offers significant improvement over the standard of care”, said Harout Semerjian, Executive Vice President, Chief Commercial Officer, Ipsen. “Ipsen remains committed to improving patients’ lives by continuing to develop new therapies and expanding the potential of Cabometyx® across different indications.”
Giuseppe Procopio, M.D., Head of the Genitourinary Unit at Fondazione Istituto Nazionale Tumori Milan, stated: “The value of treatment with Cabometyx® has been corroborated by the data generated in clinical trials, and since 2016 physicians have also witnessed the potential of it when treating patients following VEGF-targeted therapy. For both of these reasons, physicians will be pleased to soon have access to this new first-line treatment option for intermediate- or poor- risk advanced RCC patients.”
Today’s decision is based on the CABOSUN trial, which demonstrated that cabozantinib significantly prolongs progression-free survival (PFS) compared to sunitinib in treatment-naive aRCC patients with intermediate- or poor-risk. Cabozantinib is the first and only monotherapy to demonstrate superior clinical efficacy over sunitinib in treatment-naïve aRCC patients with intermediate- or poor-risk.
The detailed recommendations for the use of this product are described in the Summary of Product Characteristics (SmPC), available here (https://cabometyx.eu/).
About the CABOSUN study
On May 23, 2016, Exelixis announced that CABOSUN met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in PFS compared with sunitinib in patients with intermediate- or poor-risk aRCC per IMDC (International Metastatic RCC Carcinoma Database Consortium) criteria as determined by investigator assessment. CABOSUN was conducted by The Alliance for Clinical Trials in Oncology as part of Exelixis’ collaboration with the NCI-CTEP. These results were first presented by Dr. Toni Choueiri at the meeting of the European Society for Medical Oncology (ESMO) 2016, and published in the Journal of Clinical Oncology (Choueiri, JCO, 2018).ⁱ
On June 19 2017 Exelixis announced that the analysis of the review by a blinded independent radiology review committee (IRC) has confirmed the primary efficacy endpoint results of investigator-assessed progression-free survival (PFS) from the CABOSUN randomized phase 2 trial of cabozantinib as compared with sunitinib in patients with previously untreated advanced renal cell carcinoma (RCC) with intermediate- or poor-risk disease per the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Per the IRC analysis, cabozantinib demonstrated a clinically meaningful and statistically significant reduction in the rate of disease progression or death as measured by PFS. The incidence of adverse events (any grade) and the incidence of grade 3 or 4 adverse events between cabozantinib and sunitinib were comparable.
CABOSUN is a randomized, open-label, active-controlled phase II trial that enrolled 157 patients with aRCC determined to be intermediate- or poor-risk per IMDC criteria. Patients were randomized 1:1 to receive cabozantinib (60 mg once daily) or sunitinib (50 mg once daily, four weeks on followed by two weeks off). The primary endpoint was PFS. Secondary endpoints included overall survival and objective response rate. Eligible patients were required to have locally advanced or metastatic clear-cell RCC, ECOG performance status 0-2, and had to be intermediate- or poor-risk per IMDC criteria (Heng, JCO, 2009).ⁱⁱ Prior systemic treatment for RCC was not permitted.
About advanced Renal Cell Carcinoma
With the incidence predicted to rise 22% by 2020, renal cell carcinoma (RCC) threatens to become one of the fastest growing cancers in the world.ⁱⁱⁱ Targeted therapies including tyrosine kinase inhibitors (TKIs) of the VEGF receptor (VEGFR) introduced a decade ago, significantly transformed the treatment landscape of aRCC.^iv
The American Cancer Society’s 2017 statistics cite kidney cancer as one of the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.^v Clear cell RCC is the most common type of kidney cancer in adults.^vi If detected in its early stages, the five-year survival rate for RCC is high. For patients with advanced- or late-stage metastatic RCC, however, the five-year survival rate is only 12% with no identified cure for the disease.^vii Approximately 30,000 patients in the U.S. and 68,000 globally require treatment.^viii
The majority of clear cell RCC tumors have lower than normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL, and VEGF.^ix–^x These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness, and metastasis.^xi, ^xii, ^xiii, ^xiv MET and AXL may provide escape pathways that drive resistance to VEGFR inhibitors. xii – xv
About CABOMETYX® (cabozantinib)
Cabometyx® is an oral small molecule inhibitor of receptors, including VEGFR, MET, AXL and RET. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance.
In February of 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. This agreement was amended in December of 2016 to include commercialization rights for Ipsen in Canada. On April 25, 2016, the FDA approved Cabometyx® tablets for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy and on September 9, 2016, the European Commission approved Cabometyx® tablets for the treatment of advanced RCC in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy in the European Union, Norway and Iceland. Cabometyx® is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.
On December 19, 2017, Exelixis received approval from the FDA for Cabometyx® for the expanded indication of treatment of advanced RCC.
On May 17, 2018, Ipsen announced that the European Commission approved Cabometyx® for the first-line treatment of adults with intermediate- or poor- risk advanced renal cell carcinomain the European Union, Norway and Iceland.

Download
ⁱ “Choueiri TK, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update. Eur J Cancer. 2018;94:115-25.
ⁱⁱ Heng D.Y., Xie W., Regan M.M., et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: Results from a large, multicenter study. Journal of Clinical Oncology. 2009; 27:5794-5799.
ⁱⁱⁱ Ferlay J, Soerjomataram I, Dikshit R, et al: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359-86, 2015
^iv Jacobsen J, Grankvist K, Rasmuson T, et al. Expression of vascular endothelial growth factor protein in human renal cell carcinoma. BJU Int. 2004;93:297–302.
^v American Cancer Society. Cancer Facts & Figures 2017. Atlanta: American Cancer Society; 2017.
^vi Jonasch E., Gao J., Rathmell W.K., Renal cell carcinoma. BMJ. 2014; 349:g4797.
^vii Ko, J. J., Choueiri, T.K., et al. First-, second- third-line therapy for mRCC: benchmarks for trial design from the IMDC. British Journal of Cancer. 2014; 110: 1917-1922.
^viii Decision Resources Report: Renal Cell Carcinoma. October 2014 (internal data on file).
^ix 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):316-23.
^x 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):13373-8.
^xi Zhou L, Liu X-D, Sun M, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016;35(21):2687–2697.
^xii 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.
^xiii 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.
^xiv 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