The first drug to extend overall survival for people with advanced melanoma, the deadliest form of skin cancer, won approval today from the US Food and Drug Administration.
“You’ve got a drug that has now shown it’s a consistent winner,” says Vernon Sondak, a surgical oncologist at the H. Lee Moffitt Cancer Center in Tampa, Florida. “And it’s a winner not just in a small way but in a way that’s important to our patients by prolonging their survival.”
In a pivotal phase 3 trial of 676 patients with metastatic melanoma, the drug — a monoclonal antibody called ipilimumab developed by a New Jersey-based subsidiary of Bristol-Myers Squibb — increased lifespan by nearly four months compared to treatment with an experimental vaccine, researchers reported last year. Earlier this week, the company also announced that a combination of ipilimumab and chemotherapy improved overall survival in people with metastatic melanoma more than standard chemotherapy alone.
“There’s no question that this drug prolongs median survival,” says Mario Sznol, a medical oncologist at the Yale Cancer Center in New Haven, Connecticut where around 100 people have received ipilimumab as part of an ongoing compassionate use trial. According to Sznol, a handful of those patients have even experienced long-lasting, durable remissions. “I suspect a small number of patients are cured of their cancer with this drug,” he says.
The antibody, which will be sold under the brand name Yervoy, works by binding to and blocking the action of a key negative regulator of T-cell activation, called cytotoxic T-lymphocyte antigen 4 (CTLA4), thus allowing an immune response to be mounted against cancer cells. New York-based Pfizer has its own CTLA4-targeted antibody called tremelimumab in development, but in 2008 the company discontinued phase 3 trials after preliminary data showed that the drug was no better than standard chemotherapy in treating people with advanced melanoma. Last year, however, Pfizer, in collaboration with the Swiss-based Debiopharm Group, announced plans to relaunch clinical trials with tremelimumab, but this time using a biomarker to select patients considered likely to respond to the therapy.
Many researchers now hope that ipilimumab will also prove effective against other cancers in addition to melanoma. “It’s a new class of drug that offers new opportunities to patients with cancer in general,” says F. Stephen Hodi, a melanoma specialist at the Dana–Farber Cancer Institute in Boston who led the phase 3 trials with the immunotherapy agent. Currently, Bristol-Myers Squibb is testing ipilimumab in people with prostate cancer and lung cancer. “This is just the tip of the surface,” Sznol says.
Within a decade, some analysts predict that ipilimumab could be worth up to $1 billion per year. But convincing doctors to administer the drug could be slow going at first, notes Sondak, who was not involved in the clinical trials that formed the basis of the regulatory approval. “Now the challenge to us as physicians is to move this away from the experimental stage and into the practice arena, because it’s not a trivially easy drug to give, and it doesn’t have side effects that are similar to what we’re used to with other cancer chemotherapy drugs.”
Ipilimumab has to be given intravenously every three weeks for three months, and, since the drug ramps up the body’s immune system, it can trigger auto-immune reactions including colitis, hepatitis and impaired pituitary gland function. But from his experience running trials with the drug, Hodi notes that the side effects are within allowable limits. “Are they potentially serious? Yes. But the vast majority of cases are manageable.”
The drug may also soon face competition from other targeted agents that, instead of modulating the immune system generally, go after a specific mutated form of the B-RAF oncoprotein that has been implicated in more than half of all cases of melanoma. In January, for example, the Swiss drug maker Roche announced preliminary phase 3 trial results showing that people with advanced melanoma who received the company’s experimental B-RAF drug lived longer than those on chemotherapy. GlaxoSmithKline also launched phase 3 trials for its own B-RAF inhibitor earlier this year. For more on this approach, check out our news story from this month’s cancer focus.