Fatal Adverse Events with Pazopanib [Votrient], Sorafenib [Nexavar], and Sunitinib [Sutent]

February 12, 2012

February 12, 2012 – From an article published in Medscape Oncology News on February 9, 2012, we learn the following (article in full, all rights resting with Medscape Oncology News):

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February 9, 2012— New details on the risk for fatal adverse events associated with several targeted cancer drugs have come from a large meta-analysis of clinical trials, which was published online February 6 in the Journal of Clinical Oncology.

The drugs investigated were pazopanib (Votrient, GlaxoSmithKline), which is approved for use in renal cell carcinoma; sorafenib (Nexavar, Bayer & Onyx), which is approved for use in renal cell carcinoma and hepatocellular cancer; and sunitinib (Sutent, Pfizer), which is approved for use in hepatocellular cancer and gastrointestinal stromal tumors. All 3 products are vascular endothelial growth-factor (VEGF) receptor tyrosine kinase inhibitors.

The meta-analysis, which examined data on 4679 patients from 10 clinical trials, found that these 3 drugs were associated with fatal adverse events at a rate that was about twice that seen in the placebo groups. The crude incidence of fatal adverse events was 1.5% in patients taking these drugs, compared with 0.7% in patients in the placebo or control groups (relative risk [RR], 2.23; P = .023).

The most common cause of death was hemorrhage; the second most common was myocardial ischemia. Liver failure and congestive heart failure were also reported.

Senior author Toni Choueiri, MD, from the Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, said that clinicians need to be aware of the risks associated with these drugs.

“There is no doubt that for the average patient, these drugs have benefits,” Dr. Choueiri said in a statement. In fact, these drugs represent a major step forward in the treatment of several malignancies, and they have led to significant improvements in patient outcomes.

However, they are associated with a significant increase in the risk of developing fatal drug-related events, and “practitioners must be aware of the risks associated with their use and must provide rigorous monitoring to continue to improve patient outcomes,” the researchers note.

“While the absolute incidence of these fatal side effects is very small, the relative risks are higher,” Dr. Choueiri noted. In addition, the patients in this meta-analysis were participating in clinical trials and all had adequate organ function at study entry, so the overall incidence and risk for unreported fatal adverse events could be higher in common medical practice.


Ivacaftor [Kalydeco] approved by FDA to treat the rare G551D mutant positive form of cystic fibrosis

February 3, 2012

February 03, 2012 – From a press release by the FDA, we just learn about e new success of the principle of personalized medicine. Please read the original article below:

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The U.S. Food and Drug Administration today approved Kalydeco (ivacaftor) for the treatment of a rare form of cystic fibrosis (CF) in patients ages 6 years and older who have the specific G551D mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene.

CF is a serious genetic disorder affecting the lungs and other organs that ultimately leads to an early death. It is caused by mutations (defects) in a gene that encodes for a protein called CFTR that regulates ion (such as chloride) and water transport in the body. The defect in chloride and water transport results in the formation of thick mucus that builds up in the lungs, digestive tract and other parts of the body leading to severe respiratory and digestive problems, as well as other complications such as infections and diabetes.

CF, which affects about 30,000 people in the United States, is the most common fatal genetic disease in the Caucasian population. About 4 percent of those with CF, or roughly 1,200 people, are believed to have the G551D mutation.

“Kalydeco is an excellent example of the promise of personalized medicine – targeted drugs that treat patients with a specific genetic makeup,” said FDA Commissioner Margaret A. Hamburg, M.D. “The unique and mutually beneficial partnership that led to the approval of Kalydeco serves as a great model for what companies and patient groups can achieve if they collaborate on drug development.”

The FDA reviewed and approved Kalydeco in approximately three months under the agency’s priority review program that is designed to expedite the review of drugs. The priority review program uses a six-month review, instead of the standard 10 months, for drugs that may offer significant advances in treatment over available therapy.

Kalydeco was approved ahead of the drug’s April 18, 2012 prescription user fee goal date and is designated as an orphan drug, which identifies the disease as affecting fewer than 200,000 people in the United States.

In patients with the G551D mutation, Kalydeco, a pill taken two times a day with fat-containing food, helps the protein made by the CFTR gene function better and as a result, improves lung function and other aspects of CF such as increasing weight gain.

“Kalydeco is the first available treatment that targets the defective CFTR protein, which is the underlying cause of cystic fibrosis,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “This is a breakthrough therapy for the cystic fibrosis community because current therapies only treat the symptoms of this genetic disease.”

Two 48-week, placebo-controlled clinical studies involving 213 patients, one in patients ages 12 years and older and another in patients ages 6 years to 11 years, were used to evaluate the safety and efficacy of Kalydeco in CF patients with the G551D mutation. In both studies, treatment with Kalydeco resulted in significant and sustained improvement in lung function.

Kalydeco is effective only in patients with CF who have the G551D mutation. It is not effective in CF patients with two copies of the F508 mutation in the CFTR gene, which is the most common mutation that results in CF. If a patient’s mutation status is not known, an FDA-cleared CF mutation test should be used to determine whether the G551D mutation is present.

The most common side effects of Kalydeco include upper respiratory tract infection, headache, stomach ache, rash, diarrhea, and dizziness.


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