Over the last sixty years the incidence of malignant melanoma has skyrocketed. In 1950 one person in 2000 got melanoma; when last examined a few years ago that number was one in fifty. The graph below shows the harsh reality.
Although still only one-third the incidence of colon cancer, melanoma is a feared adversary because of its lethal reputation. Fortunately the death rate has not kept pace with the incidence because people and their doctors now recognize the early warning signs; the average melanoma is diagnosed much earlier than it used to be. Nonetheless a substantial number of people each year will develop advanced melanoma and eventual metastatic disease. Their prognosis has improved little over that of sixty years ago, despite all the advanced in chemotherapy and, more recently, targeted therapy – where small molecules attach to proteins on cell surfaces, turning off the metabolic engine of the cell.
In late March the FDA approved Ipilimumab, to be marketed as Yervoy© by Bristol-Myers Squibb, for the treatment of metastatic melanoma. There was considerable fanfare over this in the oncologic community and the press.
How helpful is it?
In the study that was submitted to the FDA as the basis for the drug’s approval, survival for patients with metastatic disease went from six months (the historical average) to ten months. Another important parameter, percent of patients surviving one year, went up substantially from 25% to 46%. When it comes to melanoma, differences like these are considered significant. Since the side-effect profile was manageable, the drug was approved. Ipilimumab boosts the body’s immune response by binding to CTLA-4, a molecule on the surface of helper T-lymphocytes, white blood cells important to the immune response. By binding to CTLA-4, it helps the body fight off the invading melanoma tumor deposits. Because of this mechanism of action, there is potential for adverse reactions to the immune system with this drug. It may take many additional patients treated before the full spectrum of side effects is appreciated.
Ipilimumab is also being tested against a host of other tumor types. Major improvements have been seen in men with far-advanced prostate cancer. It will be some time before we know whether the use of this drug will be extended to other tumor types.
Sometimes proof of principle is more important to advances in cancer therapy than the results of a single clinical trial. Manipulating the immune system is considered a key component in the fight against cancer, along with killing cancer cells outright with chemotherapy and suppressing their growth with targeted therapy. How to manipulate the immune system has been the subject of research for over thirty years, with not much to show for it until now. Perhaps modulating CTLA-4 is an important step in understanding how we can impact the growth and lethal potential of cancer.
While this was going on researchers have also been looking at a gene called B-RAF present in mutated form in melanoma cells. Targeting this mutated gene is likely to prove very important. A B-RAF drug looks very promising. I’ll report on this soon.