Targeted Therapy Could Be Key to Treatment of Malignant Melanoma Posted Wednesday, June 9, 2004 by arjuna


Medscape Medical News 2004. © 2004 Medscape

Martha Kerr

June 8, 2004 (New Orleans) — A drug that blocks both the pathway for tumor cell proliferation and for angiogenesis in malignant melanoma may finally improve the disease prognosis. Adding it to conventional chemotherapy may result in even greater success, researchers from the University of Pennsylvania in Philadelphia announced here during the 40th annual meeting of the American Society of Clinical Oncology.

Keith T. Flaherty, MD, instructor of medicine at the Abramson Cancer Center of the University of Pennsylvania, presented data on 35 patients with malignant melanoma who received the RAF kinase inhibitor BAY 43-9006, carboplatin (AUC 6), and paclitaxel 225 mg/m2. BAY 43-9006 was given orally in a dose-escalation manner at 100 mg twice daily, 200 mg twice daily, then 400 mg twice daily.

The median age of patients was 47 years. Most were nonresponders to at least one previous trial of chemotherapy.

Carboplatin and paclitaxel were given on day 1 of a 21-day cycle and BAY 43-9006 were given on days 2 through 19. Tumor samples taken previously were assessed to determine the presence of the RAF mutation, and blood samples were taken to assess pharmacokinetics. Patients were treated for at least six weeks.

Dr. Flaherty reported that 14 (40%) of the 35 patients have shown a partial response, and 40% of patients have stable disease. Overall, more than 80% of patients have shown some clinical benefit. Adverse effects were similar to those seen with carboplatin and paclitaxel therapy.

The overall response rate is significantly greater than with chemotherapy alone, Dr. Flaherty said. "Some would argue that there is no standard of care with melanoma," he told Medscape. "But responses rates with carboplatin or paclitaxel are around 15%." He added that there are very few studies using the drugs in combination, but those that have resulted in response rates of around 16% to 17%.

He pointed out that response rate for those who received a second round of chemotherapy after failing a first is extremely low in this patient population, and most of the patients in this study were nonresponders.

Of the 25 tumor samples assessed, 15 tumors (60%) showed the RAF mutation, which is "exactly" the frequency expected in melanoma, Dr. Flaherty said.

"Prospects or patients with malignant melanoma are beginning to change favorably," William W. Li, MD, president and medical director of The Angiogenesis Foundation, told Medscape. The Foundation, located in Cambridge, Massachusetts, is a nonprofit cancer research center. "Targeted therapies are largely responsible for that."

BAY 43-9006 is a multitargeting agent, blocking the vascular endothelial growth factor pathway as well as the RAF pathway, which controls cell growth and proliferation. "BAY 43-9006 is a smart bomb with multiple warheads," Dr. Li explained.

"The goal is to match the drug to the disease," Dr. Li said. Because 60% of patients with malignant melanoma carry the RAF mutation and because it is such a vascular disease, this drug could hold promise for patients with the disease, he speculated.

A major advantage of BAY 43-9006 and many other antiangiogenic agents in development is that they are oral. "We now have the potential of turning cancer into a chronic, manageable disease," Dr. Li said.

The study was funded by Bayer Pharmaceuticals.

ASCO 2004 Annual Meeting: Abstract 7507. Presented June 6, 2004.

Reviewed by Gary D. Vogin, MD
Martha Kerr is a freelance writer for Medscape.