2012 is emerging as a year in which researchers and clinicians are taking these new clinical approaches to the next level.
The two key areas are therapies targeted to specific genetic mutations and immunotherapy.
Dr. Schuchter and other melanoma experts at Penn believe we are only beginning to understand enough about how melanoma cells grow and spread to develop effective new treatments based.
Dr. Schuchter opened this year’s Focus On Melanoma Conference with an update on melanoma treatments and advances in melanoma research. Last year, the introduction of the drug vemuranefenib was the first big piece of news. Vemuranefenib works by inhibiting BRAF gene activity in the approximately 50% of melanoma patients who in whom this gene is "broken." The drug is powerful, producing often dramatic responses in patients with advanced melanoma, but it almost always stops working after a period of six to 18 months. This phenomenon --in which patients respond well to a drug for a period of time only to see the cancer come back or start growing again--is called resistance, and is one of the most perplexing barriers to developing effective, lasting cancer treatments.
Cancer researchers are beginning to understand the amazingly complex mechanisms by which cancer cells become resistant.
In the case of BRAF inhibitors, this occurs when the melanoma cells in essence take a detour--an alternate pathway that allows them to avoid the STOP growing and dividing sign they encounter when BRAF activity is inhibited. The goal now is to combine the original drug, vemuranefenib, with other targeted agents that block these alternative pathways. A major clinical trial in which vemuranefenib is used with a drug known as a MEK inhibitor is showing very promising results, and will be featured at the 2012 meeting of the American Society of Clinical Oncology (ASCO). This is one of what will be many clinical trials aimed at overcoming the problem of resistance with targeted therapies in malignant melanoma. A surprising, but welcome finding in this trial, is that the combined therapy is not only superior to vemuranefenib alone but the incidence of side effects, especially those related to skin problems, is significantly reduced.
Immunotherapy is the other very promising area in treating melanoma. Researchers have known for a long time that the immune system is active in trying to seek out and destroy melanoma cells—while on the other hand the melanoma cells are effective in hiding from the immune system. New therapies are focused on making melanoma cells more visible and increasing the level of immune activity. Last year's new agent in the immunotherapy arena is known as ipilumubab (ipi). The drug works very well for some patients, often resulting in delayed responses, meaning that in the first several weeks of therapy, the melanoma will actually grow--but then begin to regress and sometimes disappear completely. Ipi also stimulates an auto-immune response that can cause a wide range of side effects, ranging from colitis to endocrine problems to inflammations of the skin and liver.
The current goal for ipi is to understand in advance which patients should receive this drug and when. Right now, ipi is only approved for late stage melanoma patients and for a limited course of therapy. For melanoma patients at high risk of recurrence, researchers are very interested in finding out whether this drug can be effective as additional therapy once primary cancer treatment is completed (know as adjuvant therapy) -- or whether it can be used as maintenance therapy. A big question is whether ipi can be successfully combined with BRAF inhibitors— Currently they are given sequentially.
New insight in the ways in which the immune system interacts with melanoma cells is also opening the door to developing new agents and approaches to immunotherapy. PD-1 is an antibody similar to ipi which has been shown to be very active in early trials--without the autoimmune response. Another technique that is being successfully used to treat leukemias is now on the cusp of being used for melanomas as well. This involves extracting t-cells from the patient, "supercharging" them in the lab and then injecting them back into the patient--another example of an emerging new therapy that is both highly tailored and personalized.
As Dr. Schuchter said in concluding her remarks, "These are not conversations we were having nine years ago when we first started this conference. We have a lot more to do, but these are exciting times."
Watch all of the presentations from the 2012 Focus On Melanoma Conference here.
Learn more about treatment for melanoma at Penn in Philadelphia.
