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Early Study Results Demonstrate Oral Medication Active Against Skin Cancer

November / December 2003

Early results from a Phase I clinical study performed by researchers from the Abramson Cancer Center of the University of Pennsylvania show that a new kind of drug, the Raf kinase inhibitor, produces promising anti-cancer activity in patients with metastatic melanoma. The majority of patients tested showed benefits that lasted up to twelve months. Typically, metastatic melanoma is fatal within nine months, the most severe form of skin cancer. The American Cancer Society estimates that in 2003 more than 54,000 Americans will be diagnosed with melanoma and 7,600 will die from the disease.

The investigational drug, named BAY43-9006, is a pill therapy under development by Bayer and Onyx Pharmaceuticals. “It is promising to see patients do so well, this early in the research,” said Keith Flaherty, MD, an oncologist and instructor of medicine at the Abramson Cancer Center. “Melanoma is a disease that does not frequently respond to current therapies.”

Based on laboratory tests, BAY43-9006 was intended to be a broadly active cancer therapy and as such clinical trials were started two years ago. But an independent scientific discovery in June 2002 found that the target of this drug is largely responsible for the growth and development of melanoma tumors. The number of different mutations that any given cancer has is enormous, but the number that are significant is much smaller. In fact, researchers found that 70 percent of people with melanoma had a mutation in one gene that was responsible for producing Raf kinase.

Raf kinase is a key enzyme in the chain reaction of the body's chemistry that triggers cell growth. Raf kinase inhibitors are small molecules that prevent or interrupt the growth of Raf kinase. Abnormal activation of this pathway is a common thread in the development of most cancers. By blocking the action of Raf kinase, scientists hope they can reverse the progression of these tumors.

This is one of the first examples of finding a drug that works against a specific molecular abnormality and having it translate into a successful therapy. The first example is the drug Gleevac, an enzyme inhibitor for chronic myeloid leukemia, that has proven to be extremely successful.

Twenty patients enrolled in the first part of the trial where the goal was to determine a safe dosage of the Raf kinase inhibitor for use in future studies. Patients were given the Raf kinase inhibitor, twice daily - in varying doses of either 100 mg, 200 mg, or 400 mg - for a period of three weeks, in combination with two standard cancer therapies, carboplatin and paclitaxel. The safety profile of the combination therapy was determined as favorable, with minimal and reversible side effects, such as rash and diarrhea.

“Associated laboratory studies show that the Raf kinase inhibitor, at these doses, blocks the target pathway. Our next step is to continue to investigate this further in order to develop effective therapies for this life-threatening disease,” says Peter O’Dwyer, MD, professor of medicine and director of Penn’s Developmental Therapeutics Program at the Abramson Cancer Center.

Of the patients who respond to this investigational drug, many incurred a dramatic shrinking of their tumor of up to 95 percent. Through positron emission tomography (PET) scans, which detect living tumor cells, researchers found that the remaining tumor cells were not functioning. The remaining patients in this group did not experience a shrinking of their tumors but a “hollowing out,” meaning there were no living tumor cells. “If our success rate continues and participants continue to do well, this could be a remarkable therapy for melanoma,” explains Dr. Flaherty, who is a co-Principal Investigator along with Dr. O'Dwyer. “This is among the first instances of identifying the target, finding the drug and seeing the effect.”

Although the focus of this study has been on melanoma patients, BAY43-9006 is currently being tested in many different cancers including lung, kidney, colon, and pancreatic. Trial participants will continue to take the Raf kinase inhibitor and be monitored. In upcoming months, Penn researchers plan to launch a trial with other cancer centers to compare this new therapy to standard therapy. “Our strong sense is that the Raf kinase inhibitor will prove very beneficial to melanoma patients,” adds Dr. Flaherty.

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