Targeted combination therapy halts disease and extends life in advanced melanoma

A targeted combination drug therapy has shown efficacy in a study reporting major declines in the risk of disease progression and death in people with metastatic melanoma. The multicenter, double-blind, randomized, phase 3 trial compared oral dabrafenib (150 mg twice daily) and oral trametinib (2 mg once daily) combination therapy with oral dabrafenib (150 mg twice daily) and placebo.

All trial participants had inoperable stage 3C or 4 metastatic melanoma and a BRAF gene mutation V600E or V600K. Among cancer patients with metastatic melanoma, approximately 40% have a BRAF gene mutation, which is an abnormality that helps some melanoma tumors to grow and spread.

The study was led by Georgina Long, BSc, PhD, MBBS, FRACP, a medical oncologist at Melanoma Institute Australia at the University of Sydney. The finding affirms accumulating evidence of the efficacy of targeted combination therapies in extending life and halting disease progression in patients with cancers that carry genetic mutations that resist monotherapies. The study was published in the New England Journal of Medicine (2014; doi:10.1056/NEJMoa1406037).

"We show a significant 25% reduction in the risk of disease progression with the combination of dabrafenib and trametinib over single-agent dabrafenib," said Long. "We also report a significant 37% relative reduction in the risk of death among people who received the combination drug therapy compared with monotherapy.”

The research also reports that 2 in 3 patients (67%) treated with the combination therapy had a complete or partial response compared to 1 in 2 patients (51%) treated with monotherapy.

Long said, "This means that significantly more patients who received combination therapy experienced complete or partial tumor regression compared to patients who received monotherapy. Unlike standard chemotherapy, so-called BRAF-targeted therapies are designed to interact with specific molecules that are part of the pathways and processes used by cancer cells to grow, divide, and spread in the body.

Long explained that the new-generation, targeted drugs act on specific molecular targets in cancer cells that have been identified through research. This is in contrast to most standard chemotherapies, which act indiscriminately on all rapidly dividing cells. She said that these newer targeted drugs are designed to target specific vulnerabilities in the cancer cell, while most standard chemotherapies were identified through trial and error. In addition, targeted therapies tend to have fewer and less toxic side effects than standard chemotherapy because they do less damage to normal cells.

However, trials of BRAF-targeted monotherapies reveal that half the patients start to develop resistance about 6 to 7 months after starting therapy. Long said that this is why researchers are conducting trials of combination therapies that target and interrupt the mechanisms that allow cancer cells to resist monotherapies.

"Our new report confirms the accumulating evidence that targeted combination therapies can extend life and halt disease progression among people with metastatic cancer who carry genetic mutations in their cancer that resist standard chemotherapy treatments and targeted monotherapies," said Long.

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