On March 23, 2018 Ipsen (Euronext: IPN; ADR: IPSEY) reported that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA) provided a positive opinion for Cabometyx (cabozantinib) 20, 40, 60 mg for the first-line treatment of adults with intermediate- or poor- risk advanced renal cell carcinoma (aRCC).The CHMP positive opinion will now be reviewed by the European Commission (EC), which has the authority to approve medicines for the European Union (EU).
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Alexandre Lebeaut, Executive Vice President, R&D and Chief Scientific Officer said: "Today’s positive opinion from the CHMP is important news for patients with previously untreated advanced renal cell carcinoma, who can shortly benefit from Cabometyx as a new first-line treatment option. Following the evidence of its clinical value after a prior VEGF-targeted treatment, we are pleased to be able to expand the benefit of Cabometyx for treatment-naïve patients with aRCC. We would like to sincerely thank the patients and their families as well as all health care providers who took part in the CABOSUN trial and have contributed to advancing therapies to address a high unmet need in first-line treatment of intermediate- and poor-risk patients with aRCC.."
The positive CHMP opinion follows EMA approval in 2016 for the treatment of aRCC after prior VEGF-targeted therapy. The CHMP positive opinion was based on the CABOSUN trial, which demonstrated that cabozantinib prolongs progression-free survival (PFS) 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 will be described in the Summary of Product Characteristics (SmPC), to be made available once the European Commission decision is issued.
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) (Free ESMO Whitepaper) 2016, and published in the Journal of Clinical Oncology (Choueiri, JCO, 2017).[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 September 8, 2017, Ipsen announced that the EMA validated the application for cabozantinib as a treatment for first-line advanced RCC in the European Union; on March 22 2018, the CHMP issued a positive opinion for this indication.