Drug resistance is the bane of cancer researchers and patients. But early results from a new clinical trial suggest a way to get around a tumor's defenses. By combining high doses of two new drugs against advanced melanoma, scientists were able to delay for months the cancer's ability to evade the therapy aimed at a tumor's molecular weak spot.
The trial is testing a so-called BRAF inhibitor, a widely heralded new type of melanoma drug. It targets a growth-spurring protein, BRAF, encoded by a mutation in the BRAF gene that occurs in about half of melanoma patients. Although the drug extends patients' lives—on average they live 14 to 15 months, versus 8 months on conventional therapy—their tumors eventually develop resistance and begin growing again . Often the tumors restore the BRAF growth pathway by turning on a downstream protein called MEK, suggesting that combining a MEK inhibitor and a BRAF inhibitor could stave off cancer growth longer.
That strategy now shows signs of working, according to data released today in advance of the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois, from 1-5 June. In 77 patients who took a BRAF inhibitor and a MEK inhibitor made by GlaxoSmithKline, the drugs shrank tumors or delayed growth by 7.4 months on average—no longer than has been reported for the BRAF inhibitor alone. But the results were more encouraging for 24 patients who received the highest doses of the two drugs. Their tumors became stable or shrank and did not resume growing for 10.8 months on average.
That number is "impressive," said oncologist Jeffrey Weber of the Moffitt Cancer Center in Tampa, Florida, who presented the results today in a telephone and Web press conference. "Obviously we have to be cautious; it's only a cohort of 24 patients. But it looks extremely encouraging." (Results from a randomized trial that will compare the two-drug combination to a BRAF inhibitor alone are not yet available.)
"We know that cancers are smart; they find mechanisms … or workaround pathways" to evade targeted drugs, said Sandra Swain, an oncologist at Georgetown University in Washington, D.C., and president-elect of ASCO, at today's press conference. "In this case, we're seeing a very innovative approach that ostensibly blocks off some of these side pathways. So this is very exciting research that shows we're finding more and more creative ways to really precisely treat some of our most challenging cancers."
It's too soon to know if the patients will live longer overall than they would have on a BRAF inhibitor alone. Even if they do, researchers expect that resistance will eventually develop. The next step, says trial co-investigator and oncologist Keith Flaherty of Massachusetts General Hospital in Boston, is to add a third drug to the cocktail, possibly matched to another genetic weak spot in the tumor. "We're going to be in triplet territory pretty quickly," says Flaherty.
Although adding drugs often increases toxicity, patients might tolerate this triple cocktail because the two-drug combo had an unusual side benefit: It reduced the occurrence of rashes and the growth of relatively benign skin tumors  caused by a BRAF inhibitor alone.
In other ASCO news, a drug recently approved for adult lung cancer that targets a cancer growth gene called ALK has shown promise against three pediatric cancers that often have ALK mutations and can be hard to treat. Oncologist Yael Mosse of the Children's Hospital of Philadelphia reported that the drug, crizotinib (Xalkori), shrank or stabilized tumor growth in seven of eight children with anaplastic large-cell lymphoma (ALCL), two of seven patients with inflammatory myofibroblastic tumors, and 10 of 27 patients with neuroblastoma, which was linked to ALK  just 4 years ago.
Although the studies were only designed to test safety, the results for the ALCL patients, whose tumors disappeared for as long as 18 months, were "dramatic" and are already leading to a larger clinical trial, Mosse said.