New melanoma drugs - why do so few benefit?

When they work, new melanoma treatments that enlist the help of the immune system to attack tumors can have a stunning effect, in some cases arresting the deadly skin cancer for four years.

But typically just a handful of patients get that kind of response.

“We are in a situation where in some patients we see really dramatic and long-lasting effects. Some of the responses are phenomenal. Still, many patients don’t respond,” said Dr. Lynn Schuchter, a melanoma expert at the University of Pennsylvania.

“What we really are trying to understand is which patients should be treated with these drugs,” she said in an interview.

Two big drugmakers—Pfizer Inc and Bristol-Myers Squibb Co—are the farthest along in developing these drugs, but both programs have had major setbacks in the past two months.

Pfizer in April said its targeted treatment tremelimumab did not work any better than chemotherapy in a large study.

And Bristol-Myers and its partner Medarex Inc in April said they would delay seeking marketing approval of ipilimumab for advanced melanoma after U.S. regulators asked for more proof that the drug, also a targeted treatment, helps people live longer.

Pfizer and Bristol-Myers released details from studies of these drugs at a meeting of the American Society of Clinical Oncology in Chicago this week.

“There is a small subset of patients that does very well, with major complete responses or durable partial responses,” said Thomas Gajewski of the University of Chicago.

He said the problem is that on average, only about 10 percent of patients do this well, which is likely not enough to win marketing approval for the drugs.

“One of the main issues on a scientific level is to figure out who that 10 percent are,” he said in an interview.

Melanoma accounts for about 3 percent of skin cancer cases but causes most skin cancer deaths, and doctors have few effective treatments to offer once the disease has spread.

In 2008 it will be diagnosed in 62,480 Americans and will kill 8,420, according to the American Cancer Society.

IMMUNE ‘BRAKE’

Ipilimumab and tremelimumab are monoclonal antibodies—targeted immune system proteins that interfere with another immune compound called CTLA-4.

Dr. Jedd Wolchok of Memorial Sloan-Kettering in New York, who led a study for ipilimumab, describes CTLA-4 as a “brake” on immune system cells. “It is what prevents our immune system from becoming hyperactivated,” he said.

The idea behind these therapies is to temporarily release this brake in the hope that the immune system will find and destroy the cancer, Wolchok said in an interview.

Because drugs like ipilimumab work differently from chemotherapy, it may take longer to prove they work, he said.

Wolchok’s own study illustrates the point. He gave ipilimumab to 155 patients with advanced melanoma. After 12 weeks, 53 of the patients developed new tumors, meaning the cancer had progressed and a sign that the drug had failed.

The researchers continued to follow 26 of the 53 and found that in seven, the new tumors eventually shrank.

“It’s very hard for me to convince myself that those folks didn’t benefit,” Wolchok said.

Other studies of ipilimumab presented this week showed the drug improved overall survival in patients with advanced melanoma to 10 to 13 months, compared with an average of six to nine months on standard therapy.

“With these drugs, there very well may be more delayed effects,” Schuchter said.

Gajewski pointed to efforts by GlaxoSmithKline, which is using genetic profiling as a means of predicting who will benefit most from the company’s experimental immunotherapy drug MAGE-A3 ASCI for advanced melanoma.

Researchers this week said a study of biopsies of melanoma tumors taken from people before treatment uncovered a common genetic “signature” in those who later responded to MAGE-A3 ASCI.

Gajewski said molecular studies like these, which are costly and labor intensive, may reveal which patients will benefit from new immune-system therapies.

By Julie Steenhuysen
CHICAGO (Reuters)