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European Commission has approved Cabometyx for the first-line treatment of adults with intermediate- or poor- risk advanced renal cell carcinoma


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 ).

According to Giuseppe Procopio, Head of the Genitourinary Unit at Fondazione Istituto Nazionale Tumori Milan ( Italy ), the value of treatment with Cabozantinib 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.

The 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.

Cabozantinib 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.

CABOSUN met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival compared with Sunitinib in patients with intermediate- or poor-risk advanced renal cell carcinoma per IMDC ( International Metastatic RCC Carcinoma Database Consortium ) criteria as determined by investigator assessment.

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 per the IMDC criteria. Cabozantinib 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 was a randomized, open-label, active-controlled phase II trial that enrolled 157 patients with advanced renal cell carcinoma 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 ( OS ) and objective response rate ( ORR ).
Eligible patients were required to have locally advanced or metastatic clear-cell renal cell carcinoma, ECOG performance status 0-2, and had to be intermediate- or poor-risk per IMDC criteria, 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 advanced renal cell carcinoma.
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 renal cell carcinoma is high. For patients with advanced- or late-stage metastatic renal cell carcinoma, 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 VEGFR inhibitors. ( Xagena )

Source: Ipsen, 2018

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