CHICAGO A new study helps explain why up to a third of advanced melanoma patients who take Roche Holding's pill Zelboraf develop a less deadly form of skin cancer known as cutaneous squamous cell carcinoma, and points to a potential fix.
Researchers said combining drugs like Zelboraf, which block a mutation known as BRAF, with a second melanoma drug that blocks a different mutation known as MEK helped to solve this problem in lab mice.
GlaxoSmithKline has already shown early promise in a trial combining drugs that block both MEK and BRAF, and the study shows why this duo may be more effective and have fewer side effects than drugs that target either mutation separately.
Both MEK and BRAF are mutations in the same pathway and are used by the cancer to drive tumor growth.
"The combination of BRAF and the MEK inhibitors gives you a better response, and also prevents the emergence of these secondary tumors," said Professor Richard Marais of the Institute of Cancer Research in London, whose study appears in the New England Journal of Medicine.
About 50 percent of patients who get melanoma have the BRAF mutation and can be treated with Zelboraf, known generically as vemurafenib. But doctors noticed that many of these patients developed another type of skin cancer called cutaneous squamous cell carcinoma, which had to be removed surgically.
To understand why, the team -- which included researchers from the University of California, Los Angeles, Roche and Daiichi Sankyo's Plexxikon -- studied squamous cell cancer tissue from 21 malignant melanoma patients who had been treated with vemurafenib in a clinical trial.
They found about 60 percent also had RAS mutations, likely caused by sun exposure, that could predispose them to squamous cell cancer. And unlike melanoma cells, when these mutated cells became exposed to a BRAF inhibitor, they tend to grow.
"It's not that these drugs (BRAF inhibitors) are tumor promoters. What they do is accelerate growth of preexisting but asymptomatic tumors in the skin of patients who are susceptible to that disease," he said.
Treatment with a MEK inhibitor blocks this side effect, Marais said.
Tests in lab mice found that those with both types of skin cancers who were treated with a combination of a BRAF and MEK drug had fewer lesions.
And there are hints that process may work in people.
In June, GSK presented the first data from its combination BRAF and MEK inhibitors at the American Society of Clinical Oncology meeting.
"One of the things they found is the patients had fewer skin lesions. It actually works in people," Marias said.
He said the findings may spur more companies to combine their BRAF and MEK inhibitors.
"Not only will it give you the best response but it won't give you the secondary events," he said.
Melanoma globally afflicts nearly 160,000 new people each year. It can spread quickly to internal organs and average survival is six to nine months.
Zelboraf was developed in partnership with Daiichi Sankyo and is the second drug to be approved for melanoma in recent months. Prior to 2011, the U.S. Food and Drug Administration had not approved a new melanoma drug in 13 years.
SOURCE: bit.ly/zAkxlQ New England Journal of Medicine, online January 19, 2012.