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Stivarga for the treatment of gastrointestinal stromal tumors approved in the European Union


Stivarga ( Regorafenib ) has been approved by the European Commission ( EC ) for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumors ( GIST ) who progressed on or are intolerant to prior treatment with Imatinib and Sunitinib.
The approval of Stivarga in GIST is based on results from the pivotal phase III study ( GRID ) that has demonstrated a statistically significant improvement in progression-free survival, compared to placebo, in patients with GIST whose disease had progressed after prior treatments.
Stivarga is already approved in the European Union for the treatment of patients with metastatic colorectal cancer ( mCRC ).

The results of the pivotal phase III GRID trial has showed that Regorafenib plus best supportive care ( BSC ) significantly improved progression-free survival compared to placebo plus BSC ( hazard ratio, HR=0.268; p less than 0.0001 ) in patients with metastatic and/or unresectable GIST who were previously treated with Imatinib and Sunitinib, reducing the risk of progression or death by 73%.
The median progression-free survival was 4.8 months in the Regorafenib arm versus 0.9 months in the placebo arm ( p less than 0.0001 ).
The increase in progression-free survival was consistent and independent of patient age, sex, geographic region, prior lines of treatment or ECOG performance status.

In clinical trials, the most frequently reported drug-related adverse events in Regorafenib-treated patients versus placebo-treated patients, respectively, were: asthenia / fatigue, hand-foot skin reaction / palmar-plantar erythrodysesthesia , diarrhea, decreased appetite and food intake, hypertension, mucositis, dysphonia, infection, pain ( not otherwise specified ), decreased weight, gastrointestinal and abdominal pain, rash, fever and nausea.
The most serious adverse drug reactions in patients receiving Regorafenib are hepatotoxicity, hemorrhage, and gastrointestinal perforation.
Adverse events in Regorafenib-treated patients generally occur early ( within the first two treatment cycles ), therefore it is advised to monitor patients closely.

Regorafenib is an oral multi-kinase inhibitor that inhibits various kinases within the mechanisms involved in tumor growth and progression – angiogenesis, oncogenesis and the tumor microenvironment.
In preclinical studies, Regorafenib has inhibited several angiogenic VEGF receptor tyrosine kinases that play a role in tumor neoangiogenesis ( the growth of new blood vessels ).
In addition to VEGFR 1-3 it also inhibits various oncogenic and tumor microenvironment kinases including TIE-2, RAF-1, BRAF, BRAFV600, KIT, RET, PDGFR, and FGFR, which individually and collectively impact upon tumor growth, formation of a stromal microenvironment and disease progression.

GIST is the most common form of sarcoma arising from the muscle wall of the gastrointestinal tract. GIST represents a life-threatening malignancy if the disease has spread to other parts of the body ( metastasized ) or is unable to be surgically removed with curative intent.
GIST affects an estimated 11-20 patients per million per year worldwide.
The discovery of oncogenic KIT kinase mutations in GISTs and the introduction of kinase inhibitor therapies have led to a rapid evolution in the understanding of these tumors. It is now established that 70–80% of GISTs harbor a KIT gene mutation, that these mutations lead to the continued activation of the kinase and that mutant KIT is a clinically important therapeutic target in GIST. ( Xagena )

Source: Bayer, 2014

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