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FDA Approves Two New PGx Drugs, Companion Test for Advanced Melanoma Patients

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Two new personalized treatment options are now available for patients with metastatic or unresectable melanoma whose tumors harbor mutations in the BRAF gene.

The US Food and Drug Administration this week approved GlaxoSmithKline's Tafinlar (dabrafenib) and Mekinist (trametinib). Both drugs have been approved with a companion test that gauges BRAF mutations in patients, called the THxID BRAF Kit, developed by BioMérieux.

Specifically, the BRAF inhibitor Tafinlar treats melanoma patients whose tumors have BRAF V600E mutations. Mekinist, a MEK inhibitor, is indicated to treat patients who express the BRAF V600E or V600K mutations. The THxID BRAF Kit gauges both V600E and V600K mutations.

GSK filed for regulatory approval for Tafinlar and Mekinist last August. Data on BioMérieux's test, as it was used to screen patients for BRAF mutations ahead of enrollment in clinical trials involving Tafinlar and Mekinist, was also submitted to the FDA.

According to National Cancer Institute estimates, this year more than 75,000 people in the US will be diagnosed with melanoma, and more than 9,000 patients will die from the disease. Around half of melanoma patients have BRAF mutations, and more than 90 percent of BRAF mutations are BRAF V600E mutations.

In a statement, Richard Pazdur, director of FDA's Office of Hematology and Oncology Products, pointed out that Tafinlar and Mekinist represent the third and fourth drugs the agency has approved for metastatic melanoma in the past two years.

In 2011, the FDA approved Roche/Genentech's Zelboraf (vemurafenib), a BRAF inhibitor that's indicated for patients who harbor BRAF V600E mutations. Last year, long-term survival data from a Phase I extension study involving 32 patients showed that 55 percent of patients treated with Zelboraf were alive after one year, 36 percent after two years, and 26 percent after three years of treatment.

Also in 2011, the agency approved Bristol-Myers Squibb's Yervoy (ipilimumab) for advance melanoma patients.

The FDA approved Tafinlar based on a Phase III study involving 250 patients with metastatic or unresectable melanoma whose tumors harbored the BRAF V600E mutation, as established by the THxID test. Study participants were randomized to receive Tafinlar or the chemotherapy agent dacarbazine. The study showed that Tafinlar-treated patients experienced a 2.4 month longer delay in tumor growth compared to chemo-treated patients (PGx Reporter 6/6/2012).

Serious side effects associated with Tafinlar include increased risk of cutaneous squamous cell carcinoma (a kind of skin cancer), fevers complicated by low blood pressure, chills, dehydration, kidney failure, and increase blood sugar that requires changes in diabetes medications. Common side effects of the drug were thickening of the skin, headache, fever, joint pain, and non-cancerous skin tumors.

The agency approved Mekinist based on a Phase III study involving 322 patients with metastatic or unresectable melanoma who had BRAF V600E- or V600K-mutated tumors. Patients were randomized to receive either Mekinist or chemo, which resulted in Mekinist-treated patients experiencing a 3.3-month longer delay in tumor growth compared to chemo-treated patients. Patients treated with Tafinlar or other BRAF inhibitors didn't benefit from Mekinist in the trial.

In the study, serious side effects seen in patients receiving Mekinist included heart failure, lung inflammation, skin infections, and vision loss. Common side effects of the drug were rash, diarrhea, peripheral edema, and acne-like skin breakouts.

These two drugs may cause infertility, the agency warned, and noted that doctors should advise women of child-bearing years that Tafinlar and Mekinist could potentially harm a fetus.

Although BRAF and MEK inhibitors have shown to delay cancer progression in patients with BRAF mutations, patients treated with single agents eventually experience disease recurrence. GSK is investigating whether combining a BRAF and MEK inhibitor can battle patients' acquired resistance to single agents or can reduce treatment-related toxicities.

Earlier this year, GSK announced the launch of COMBI-AD, a Phase III trial studying whether Tafinlar and Mekinist as adjuvant therapy can delay or prevent the recurrence of melanoma in patients with advanced disease and BRAF V600E- and V600K-mutated tumors that have been completely surgically removed.

The drug combination is also being studied in a Phase III trial in BRAF V600E/K mutation positive melanoma patients with unresectable disease who haven't received treatment for their advanced cancer. This study will compare the progression-free survival and survival in patients treated with Tafinlar/Mekinist combination or just Tafinlar.

A third Phase III study is investigating the drug combo and comparing it to Zelboraf in more than 600 cutaneous melanoma patients with unresectable, advanced disease, with BRAF V600E- or V600K-positive tumors. The primary endpoint for this study is overall survival.

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