Two experimental GlaxoSmithKline Plc (GSK) drugs that block genes tied to lethal skin cancer worked better than chemotherapy in studies that tested them individually, paving the way for final-phase trials on their use together.
About 80 percent of patients with advanced melanoma given Glaxo’s trametinib were alive after six months, compared with 67 percent on chemotherapy used as a standard treatment. Separately, Glaxo’s dabrafenib (PX030525:US) delayed disease progression by 5.1 months, compared with 2.7 months for chemotherapy. The Glaxo-funded research is being reported today at the American Society of Clinical Oncology meeting in Chicago.
The individual research followed an early-stage study in 77 patients that found the drugs used together resulted in fewer skin lesions than previously reported with Roche Holding AG (ROG)’s Zelboraf, a therapy cleared last year that targets a mutant gene found in half of advanced melanoma cases. Glaxo has begun two final-stage trials on the combo therapy, the company said.
The combination “is where we have the most enthusiasm right now,” said Keith Flaherty, director for developmental cancer therapeutics at Massachusetts General Hospital in Boston, and an author on the trametinib study. It “looks better in terms of efficacy, and better in terms of safety.”
The U.S. will have an estimated 76,250 new cases of melanoma this year, with 9,180 deaths, according to the National Cancer Institute. While patients with early-stage disease respond well to treatment, the five-year survival rate for those with cancer that has spread is 15 percent, according to the American Cancer Society.
Approval of the two Glaxo drugs could generate as much as 1.5 billion pounds ($2.35 billion) in 2020, said Andrew Baum, a London-based analyst at Citigroup Inc., said in a note to investors last week. The company will seek regulatory approval of both compounds individually later this year.
In an interview, Paolo Paoletti, president of the oncology unit for London-based Glaxo, said his company has begun two late-stage trials of the combination therapy in advanced skin cancer. One will compare the combination to dabrafenib alone; the other compares the combo to Roche’s Zelboraf.
“We are rolling; the interest is so great the enrollment will be very quick,” said Paoletti. If the benefits of teaming the two drugs hold up, “it is a transformation. It will be a new standard of care.”
Zelboraf and Glaxo’s dabrafenib work by blocking BRAF, a mutant gene that spurs cancer cell growth in about half of melanoma patients. Zelboraf was approved in the U.S. in August 2011. Trametinib is designed to thwart a related protein called MEK that helps tumors resist an assault on BRAF.
With few side effects, the combination therapy could become the industry “gold standard” in treating melanoma patients with the BRAF mutation as early as 2014, CitiGroup’s Baum said.
One downside of the BRAF-blocking drugs is that using them may activate certain growth pathways in healthy cells, leading to non-melanoma skin cancers. Adding the MEK drug can block the formation of these skin lesions, it turns out, Flaherty said.
Finding out that a second drug can cancel out the side effects of the first “was the cool part,” Glaxo’s Paoletti said. “Usually, when you combine two drugs they increase toxicity.”
Glaxo’s move into combination trials was “so gutsy,” said George Demetri, an oncologist at Dana Farber Cancer-Institute in Boston. “Glaxo did a spectacular job.” Demetri said he was a scientific adviser for one of Roche’s partners in the development of Zelboraf.
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