Melanoma has a bad rep -- and rightfully so! Metastatic melanoma remains a difficult cancer to treat. Historically, it is been considered an incurable cancer. In the words of Dr. George Canellos of the Dana-Farber Cancer Center in Boston, "Melanoma is the tumor that gives cancer a bad name."
What’s the latest in treatment for advanced melanoma?
The landscape for treatment of advanced melanoma is expanding. In fact, 2011 was a great year for melanoma treatment with the FDA approval of two drugs for the treatment of advanced disease, ipilimumab (Yervoy) and vemurafenib (Zelboraf).
These agents are very different from traditional anti-cancer therapy, so understanding how these drugs work (never mind learning how to say their names) is absolutely essential to being able to consult on toxicity, logistics of administration, and expectations.
Ipilimumab is the first agent to demonstrate an increase in overall survival in any randomized Phase III trial, ever, in the treatment of advanced melanoma.
Ipilimumab is an immunotherapy, an anti-CTLA-4 antibody. CLTA-4 are the “brakes” on a T-cell. Specifically, ipilimumab blocks CTLA-4 or “takes the brakes off the immune system.” By removing the brakes, the power of the T-cells are unleashed. The hope is, without the leash, these T-cells will attack the melanoma cells and ultimately destroy them.
Now, getting these cells to destroy cancer cells is one thing, but when that leash is off… those T-cells can go wild! When that happens, they attack normal cells and the patient will experience autoimmune effects such as dermatitis, uveitis, colitis, hepatitis, and, rarely, endocrinopathies such as hypophysitis. These “-itises” represent inflammatory response from the ipi, which is the goal -- but, as they say, ”too much of a good thing isn’t good at all.”
This agent has potential toxicity that must be evaluated for on a regular basis, and lots of patient education must be provided to the patient to ensure he or she reports symptoms! Risk/benefit must be clearly described to any potential patients. Having said that, there are many patients in my own practice alive today because of this agent.
Melanoma researchers have been busy. Over the past decade or so, there has been a much more detailed understanding of how melanoma evolves, which has led to the development of targeted agents that inhibit key pathways on which the growth and survival of a particular cancer depend.
The BRAF protein is normally involved in regulating cell growth, and in about 50 percent of all metastatic melanoma, this protein was found to be mutated (it is mutated in other cancers as well… but that is for another blog). Vemurafenib (Zelboraf) is a BRAF inhibitor that blocks the function of this mutated BRAF protein. Results from a randomized Phase III international trial demonstrated a 63 percent decrease in risk of death, compared to those who received the standard chemotherapy, dacarbazine. These findings led to vemurafenib's FDA approval this past summer for patients with a BRAF mutation.
Toxicity is generally mild, rash and myalgias being the most common side effects, however this agent can also prolong Q-T-C interval, so caution is required with underlying cardiac issues. Also, the development of cutaneous squamous cell carcinomas is seen in about 26 percent of patients. Therefore skin examinations need to be part of regular assessments. What is most exciting is that this agent works quickly in most cases. Symptomatic patients can often feel better, with noticeable tumor shrinkage and decrease in symptoms in days!
Until this past year, treatment options for advanced melanoma were extremely limited, and none ever demonstrated a survival benefit; that is no longer true. These two agents, though not right for every patient, are effective treatment options for select patients, with a real chance of offering meaningful benefit.