Melanoma is an aggressive form of skin cancer that begins in the pigment-forming cells of the skin called melanocytes. While melanoma accounts for less than 5 percent of all skin cancers, it is far more serious than other skin cancers if not detected and treated early, before it has a chance to metastasize, or spread, to nearby lymph nodes and organs. Once the cancer has spread, the chances of achieving treatment success drop significantly. Recently, preliminary findings from a study led by Memorial Sloan-Kettering investigators have revealed rapid and dramatic shrinking of metastatic tumors in patients treated with a new compound that interrupts a tumor-growth pathway present in the majority of patients with melanoma.
Turning Melanoma “On” and “Off”
Mutations in the BRAF gene are present in approximately 50 to 60 percent of patients with melanoma, and in a minority of patients with colon, breast, and lung cancers. Mutant BRAF proteins play a central role in the growth and survival of cancer cells — “turning on” a metabolic pathway known as MAPK, which in turn leads to tumor growth. Since 2004, Memorial Sloan-Kettering researchers have been testing new drugs designed to turn off this pathway, with the aim of stopping melanoma from growing.
Memorial Sloan-Kettering investigators and colleagues from five other institutions — University of Pennsylvania, Vanderbilt University, University of California, Los Angeles, M.D. Anderson Cancer Center, and Peter MacCallum Cancer Center, in Melbourne, Australia — have conducted a phase I trial of the BRAF-inhibitor drug PLX4032. Unlike standard chemotherapy, which attacks the machinery involved in cell division, PLX4032 targets the underlying genetic program that is believed to be causing the uncontrolled cell growth by targeting mutant BRAF proteins.
In preliminary results from metastatic melanoma patients with the BRAF mutation, 19 of the 27 patients who have been evaluated so far had their tumors shrink by a minimum of 30 percent taking 960mg of PLX4032 by mouth two times a day.
“Of the 27 patients we have been able to evaluate so far, almost all have had some objective tumor shrinkage, and 70 percent qualified as a true partial or complete response,” says Paul Chapman, MD, one of the leaders of the trial and a medical oncologist specializing in the treatment of melanoma at Memorial Sloan-Kettering. “This is particularly impressive because they all had metastatic disease and most of them had failed prior therapies.”
“A lot of these patients were pretty sick, but many of them had a significant and rapid improvement in their function.”
Paul Chapman, MD
The initial responses were immediate and in some cases dramatic. “A lot of these patients were pretty sick, but many of them had a significant and rapid improvement in their function,” Dr. Chapman explains. “Some individuals were able to come off oxygen, and several have been able to stop taking narcotic pain medication soon after starting the PLX4032 treatment.”
Caveats and Possible Side Effects
Dr. Chapman notes that since the study results are preliminary, it is unclear at present how long these positive responses will last. In addition, there are a number of possible side effects, including fatigue, joint pain, heightened sensitivity to light, elevated levels of liver enzymes, and an increased risk of another type of skin cancer known as squamous cell carcinoma. “We are very vigilant about tracking squamous cell skin cancers,” Dr. Chapman emphasizes. “Although these non-melanoma skin cancers are easily treated with surgery alone, we are working to understand the mechanism that is driving their development in a minority of patients taking PLX4032.”
To answer these and other questions raised by the initial studies, Dr. Chapman and colleagues are planning a second phase II trial of 90 patients, scheduled to begin at the end of 2009. Additionally, a large phase III randomized controlled clinical trial involving several hundred patients is planned to begin by early 2010 at cancer centers in North America, Europe, and Australia.