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The European Medicines Agency ( EMA ) has validated the application for variation to the Cabometyx ( Cabozantinib ) marketing authorization for the addition of a new indication in first-line treatment of advanced renal cell carcinoma ( aRCC ).

The filing is based on the results of CABOSUN, a phase II trial demonstrating that Cabozantinib prolongs progression free survival ( PFS ) in treatment-naive patients with intermediate- or poor-risk aRCC compared to Sunitinib, the standard of care for more than 10 years.
If approved, Cabometyx would be the first and only single-agent treatment to demonstrate superior clinical efficacy over the standard of care in both first line ( vs. Sunitinib ) and second line ( vs. Everolimus ) aRCC.

In September 2016, Cabometyx was approved in the European Union for the treatment of aRCC in adults following prior vascular endothelial growth factor ( VEGF )-targeted therapy.

Cabometyx is the tablet formulation of Cabozantinib. Its targets include MET, AXL, and VEGFR receptors in tumor cells. 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.
Cabometyx is available in 20 mg, 40 mg, or 60 mg doses. The recommended dose is 60 mg orally, once daily.

On May 23, 2016, Exelixis announced that CABOSUN met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival ( 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.

On June 19th 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 from the CABOSUN randomized phase 2 trial of Cabozantinib as compared with Sunitinib in patients with previously untreated advanced renal cell carcinoma with intermediate- or poor-risk disease according to IMDC criteria.
For IRC analysis, Cabozantinib has demonstrated a clinically meaningful and statistically significant reduction in the rate of disease progression or death as measured by progression-free survival.
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 progression-free survival. 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 ).
Prior systemic treatment for renal cell carcinoma was not permitted.

With the incidence predicted to rise 22% by 2020, renal cell carcinoma threatens to become one of the fastest growing cancers in the world.
Targeted therapies including tyrosine kinase inhibitors ( TKIs ) of the VEGF receptor ( VEGFR ) introduced a decade ago, significantly transformed the treatment landscape of aRCC.
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.
Clear cell RCC is the most common type of kidney cancer in adults. 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.
Approximately 30,000 patients in the U.S. and 68,000 globally require treatment.
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. These proteins promote tumor angiogenesis, growth, invasiveness, and metastasis. MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors. ( Xagena )

Source: Ipsen, 2017

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