The roller coaster ride of melanoma drug development

This week, the New York Times is tracing the Phase I testing of a novel melanoma drug being developed by Plexxikon and Roche.  The paper says to chronicle the three years of PLX4032 testing "is to ride a roller coaster of breakthroughs and setbacks at what many oncologists see as a watershed moment in understanding the genetic changes that cause cancer."

PLX4032 is an oral, highly selective drug that targets the cancer-causing BRAF mutation, which occurs in about 50 percent of melanomas, 10 percent of colorectal cancers and overall, 8 percent of all solid tumors. The drug was tested in Phase I by Dr. Keith Flaherty, the focus of the article.

In 2002, Flaherty read that B-RAF mutation is present in many melanomas, and he hypothesized that a drug that blocked the protein made by the defective gene might work. With the blessing of his superiors at the University of Pennsylvania's melanoma clinic--and despite the skepticism of other oncologists--he enrolled several hundred patients in a trial of in targeted therapy now owned by Bayer. But the drug proved ineffective in these melanoma patients.

However, Plexxikon was watching Flaherty and invited him to test PLX4032, which was being developed through a 2006 agreement with Roche. Initially, the drug didn't shrink the tumors, but Flaherty and collaborator Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center convinced the companies that Roche would have to reformulate the drug. Plexxikon and Roche agreed to this despite the delay incurred in advancing the drug to Phase II.

Flaherty and Chapman's persistence paid off. Last June, three years after they approached Flaherty, Plexxikon and Roche detailed successful preliminary Phase I results from 55 patients. Disease control lasted up to 14 months with continuous therapy, with many patients still receiving treatment, according to a statement. A pivotal Phase II clinical trial for the treatment of metastatic melanoma began in September 2009, and a Phase III study started in December.

- read the Plexxikon statement on the Phase I results
- check out the NYT coverage