A widely hailed new drug for melanoma, which was tested in combination with another drug to boost its tumor-fighting power, has done well in a key safety trial. According to a press briefing today at the American Society for Clinical Oncology's (ASCO's) annual meeting in Chicago, Illinois, the new study is an important test case of a hot area in cancer research—combining molecularly targeted drugs.
Targeted cancer therapies have strengths and weaknesses. They home in on a tumor's weak spot, often a faulty protein that signals a cell's nucleus to divide. The most famous such drug, Gleevec, has saved the lives of many patients with chronic myeloid leukemia. But as noted in a recent Science news story, targeted therapies don't work as well on solid tumors, which usually develop resistance and start growing again.
The study was inspired in part by the complex effects of a new melanoma drug developed by the biotech companies Plexxikon and Roche that blocks a protein made by a mutated gene called BRAF. While patients often improve on the drug and live longer than they would on standard treatment (results will be presented Sunday at ASCO), the drug, vemurafenib, usually stops working within a year.
By analyzing tumor biopsies from patients who relapsed on vemurafenib, researchers are learning how tumors become resistant: Often they restore the growth pathway that the drug blocks by activating a protein further downstream called MEK. That observation inspired GlaxoSmithKline, which also makes a BRAF inhibitor, to combine this drug with a MEK inhibitor.
Early results to be presented at ASCO look good. When 45 cancer patients, most with advanced melanoma, took a cocktail of the BRAF and MEK inhibitors, there were few significant side effects. This held true even in a subset who got full doses of both drugs. That is "very unusual for a combination," which often is more toxic than either drug alone, says presenter Jeffrey Infante of the Sarah Cannon Research Institute in Nashville, Tennessee, who will present on Monday.
In fact, in this case, two common side effects of the BRAF inhibitor--rashes and a different type of skin cancer—were rare in patients taking the drug cocktail. The skin lesions apparently occur because the BRAF drug activates the MEK pathway in normal cells, spurring growth. Animal studies suggested that adding a MEK inhibitor would dampen this effect, and the clinical trial has now "reaffirmed our hope," says trial co-investigator Keith Flaherty of Massachusetts General Hospital in Boston.
The drug cocktail also appears to thwart melanoma: Of sixteen patients evaluated in the second stage of the trial, 13 saw their tumors shrink and three remained stable. That is roughly comparable to the results for a BRAF inhibitor, Infante says.
It's not yet known whether patients will survive longer than they would on the BRAF inhibitor alone. Fifty patients have enrolled in a study to answer that question; the results won't be available for at least a year.
*The date of the presentation has been corrected.