The US Food and Drug Administration today approved the first of a new class of skin cancer drugs aimed at a common mutation implicated in driving tumor growth.
The oral targeted therapy, marketed as Zelboraf (vemurafenib) by Genentech of South San Francisco and Daiichi Sankyo of Japan, was given the nod more than two months ahead of schedule to treat metastatic melanoma in people harboring a mutated form of the B-RAF oncogene. Alongside the drug, the FDA also approved Roche Molecular System’s companion diagnostic test for the mutation.
“The new age of cancer therapeutics has been ushered into melanoma with this drug,” says cancer genome researcher Levi Garraway of the Dana-Farber Cancer Institute in Boston. “An age where it’s not solely about where in the body the cancer arose, but the importance of genetics in the tumor holds the decisive seat at the table.”
Around half of all people whose melanoma metastasizes develop a specific point mutation in their B-RAF gene. This mutation ramps up the activity of the encoded protein, stimulating a growth pathway that causes the cancerous cells to multiply unchecked. Zelboraf, which the Wall Street Journal reports will cost around $56,400 for a six-month treatment, works by inhibiting the mutant protein, preventing activation of the signaling cascade.
In a 675-person trial published in the New England Journal of Medicine in June, a team led by Paul Chapman of Memorial Sloan-Kettering Cancer Center in New York found that the chances of cancer return and cancer death decreased by 74% and 63%, respectively, in those participants taking Zelboraf with chemotherapy compared to people on chemotherapy alone. This dramatic result compelled the study team to end the study early to allow all participants to begin taking the targeted drug.
“It’s so nice, after 15 years of unsuccessful clinical trials, to actually have a trial to show that you can keep a disease under control and get it under control very quickly,” says oncologist Anna Pavlick, co-director of the melanoma program at New York University’s Langone Medical Center who was involved in Zelboraf’s development. “The drug is changing how long [patients] live with a good quality of life and I think that’s really the bottom line.”
However, Zelboraf isn’t without its caveats: first and foremost, the majority of tumors develop resistance to this and other B-RAF inhibitors within six to eight months of treatment. To get around this problem, doctors hope to attack the cancer from multiple angles — and, fortunately, another innovative melanoma drug called Yervoy (ipilimumab) also gained approval earlier this year. Yervoy, developed by New York’s Bristol-Myers Squibb, is an antibody that blocks a key negative regulator of T-cell activation to stimulate an immune response against cancer cells.
“There is reason to be particularly excited about combination strategies with these two drugs,” says David Fisher, the director of the melanoma program at Massachusetts General Hospital Cancer Center in Boston. Taken together, they may be able to do what neither can do alone — cure metastatic melanoma. “We expect the different mechanisms to sum their activities and theoretically clear the entire population,” he says. Roche/Genentech and Bristol-Myers Squibb have already planned a clinical trial to test the two drugs together.
Cure or no cure, Zelboraf serves another purpose for the research community: a proof-of-concept that gene-specific therapies can work. “For the many other devastating cancers where we don’t have drugs like this, this is a huge message,” says Fisher. “Just a few years ago, that’s where the melanoma field was. It’s all about identifying the right targets and coupling those to the right drugs.”