SATURDAY, Sept. 29 (HealthDay News) -- Researchers say they've discovered a two-drug combination that delays treatment resistance in patients with advanced melanoma.

By targeting different points in the same growth-factor pathway, the kinase inhibitor drugs dabrafenib and trametinib postponed the development of drug resistance in patients with BRAF-positive metastatic melanoma, the study authors said.

Melanoma is the most serious, and often deadly, form of skin cancer. In about half of patients with melanoma that has spread, tumor growth is caused by genetic mutations that keep the BRAF protein -- part of the MAPK cell growth pathway -- constantly activated. Drugs that inhibit BRAF activity can rapidly stop and reverse tumor growth in about 90 percent of patients. But the response is temporary in most cases, and tumor growth resumes in six or seven months, the researchers explained.

Previous research suggested that this drug resistance develops because the MAPK pathway gets turned back on through activation of MEK, another protein that is part off the MAPK pathway.

"We investigated this (drug) combination because of research we and others have conducted into the molecular underpinnings of resistance to BRAF inhibitor therapy," study lead author Dr. Keith Flaherty, of the Massachusetts General Hospital Cancer Center, said in a hospital news release.

The phase 1 and 2 study was sponsored by GlaxoSmithKline, which developed both drugs.

"We found that adding the MEK inhibitor trametinib to BRAF inhibitor dabrafenib clearly delays the emergence of resistance. In fact, the combination was at least twice as effective as BRAF inhibition alone," he said.

Read More...

GlaxoSmithKline Plc (GSK)’s combination of two experimental melanoma medicines slowed the cancer’s progress longer than a single-drug treatment, a study found.

Patients taking Glaxo’s dabrafenib and trametinib together delayed tumors from progressing for 9.4 months, compared with 5.8 months for patients taking dabrafenib alone, according to the study of 162 patients. The trial was part of the second of three phases of human testing usually required by regulators.

Dabrafenib works by blocking BRAF, a mutant gene that spurs cancer-cell growth in about half of melanoma patients, while trametinib thwarts a related protein called MEK, which helps tumors resist an assault on BRAF. The study, funded by London- based Glaxo, was released today at the European Society for Medical Oncology meeting in Vienna and simultaneously published in the New England Journal of Medicine. Read More...

SATURDAY, Sept. 29 (HealthDay News) -- Researchers say they've discovered a two-drug combination that delays treatment resistance in patients with advanced melanoma.

By targeting different points in the same growth-factor pathway, the kinase inhibitor drugs dabrafenib and trametinib postponed the development of drug resistance in patients with BRAF-positive metastatic melanoma, the study authors said.

Melanoma is the most serious, and often deadly, form of skin cancer. In about half of patients with melanoma that has spread, tumor growth is caused by genetic mutations that keep the BRAF protein -- part of the MAPK cell growth pathway -- constantly activated. Drugs that inhibit BRAF activity can rapidly stop and reverse tumor growth in about 90 percent of patients. But the response is temporary in most cases, and tumor growth resumes in six or seven months, the researchers explained.

Previous research suggested that this drug resistance develops because the MAPK pathway gets turned back on through activation of MEK, another protein that is part off the MAPK pathway.

"We investigated this (drug) combination because of research we and others have conducted into the molecular underpinnings of resistance to BRAF inhibitor therapy," study lead author Dr. Keith Flaherty, of the Massachusetts General Hospital Cancer Center, said in a hospital news release.

The phase 1 and 2 study was sponsored by GlaxoSmithKline, which developed both drugs.

"We found that adding the MEK inhibitor trametinib to BRAF inhibitor dabrafenib clearly delays the emergence of resistance. In fact, the combination was at least twice as effective as BRAF inhibition alone," he said.

One expert agreed that the results were encouraging.

"This study addresses the problem of resistance to the mitogen-activated protein kinase [MAPK] pathway. This study combined dabrafenib [a selective BRAF inhibitor] and trametinib, [a selective MAPK kinase (MEK) inhibitor]. These drugs can be safely combined, and the survival was significantly improved without untoward side effects," said Dr. Michele Green, a dermatologist at Lenox Hill Hospital in New York City.

The study was conducted at 14 sites in the United States and Australia and included 162 patients who received different dose combinations of the drugs: two daily 150 milligram (mg) doses of dabrafenib plus one 2 mg dose of trametinib; the same dabrafenib dose with a 1 mg dose of trametinib; or treatment with dabrafenib alone.

Patients who received dabrafenib alone were able to receive the full-dose combination treatment if their cancer resumed progression.

Treatment with both combinations of dabrafenib and trametinib led to a four-month longer delay in drug resistance than treatment with dabrafenib alone. After one year of treatment, 41 percent of patients receiving the full-dose combination treatment had no progression of their melanoma, compared with 9 percent of those receiving dabrafenib alone.

Among patients receiving the combination treatment, the development of side effects such as skin rash and a less dangerous type of skin cancer called squamous cell carcinoma was similar to that typically seen in patients taking only one of the drugs.

The study was scheduled for presentation Saturday at the European Society for Medical Oncology meeting in Vienna and simultaneous publication in the New England Journal of Medicine.

The drug combination is now being tested in a larger phase 3 study, which is required for U.S. Food and Drug Administration approval.

SOURCE: Michele Green, M.D., dermatologist, Lenox Hill Hospital, New York City; Massachusetts General Hospital, news release, Sept. 29, 2012

HealthDay

MONDAY, Oct. 1 (HealthDay News) -- For patients with metastatic melanoma with BRAF V600 mutations, combination therapy with a selective BRAF inhibitor (dabrafenib) and a mitogen-activated protein kinase inhibitor (trametinib) is tolerable and active, according to a study published online Sept. 29 in the New England Journal of Medicine to coincide with presentation at the annual meeting of the European Society for Medical Oncology, held from Sept. 28 to Oct. 2 in Vienna.

Keith T. Flaherty, M.D., from the Massachusetts General Hospital Cancer Center in Boston, and colleagues conducted an open-label phase 1 and 2 study involving 247 patients with metastatic melanoma and BRAF V600 mutations. The pharmacokinetic activity and safety of oral dabrafenib and trametinib was assessed in 85 patients, and 162 patients were randomly allocated to either dabrafenib plus trametinib or dabrafenib monotherapy. Read More...

National report — A two-drug combination for metastatic melanoma reduced the odds of progression by 60 percent, demonstrating more effectiveness than monotherapy, according to researchers.

The study demonstrated that the BRAF-inhibitor dabrafenib and the MEK-inhibitor trametinib resulted in a median progression-free survival of 9.4 months compared to 5.8 months for patients who received only dabrafenib, MedPage Today reports. Researchers from institutions around the United States enrolled 247 patients with metastatic melanoma who had histologically confirmed metastatic melanoma with either BRAFV600E or BRAFV600K mutations, but had not received previous BRAF-inhibitor treatment.

The authors randomly assigned patients to receive 150 mg of dabrafenib twice daily plus once-daily trametinib, at a dose of either 1 mg (combination 150/1) or 2 mg (combination 150/2), or 150 mg of dabrafenib monotherapy twice daily. The combined dose of 150 mg of dabrafenib and 2 mg of trametinib led to a lower incidence of squamous cell carcinoma (7 percent) compared to monotherapy (19 percent) and a higher complete or partial response compared to monotherapy (76 versus 54 percent). Read More

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