Melanoma drug PLX4032 has set the cancer world abuzz more than once over the past year and a half. And with an interim analysis of a Phase III trial released yesterday that showed both an overall survival benefit and a progression-free survival benefit for patients taking the drug as a first-line agent, it is doing it again.
The 675-patient BRIM 3 study is the first where PLX4032, which also goes by the name RG7204, was used as a first-line agent for BRAF mutation positive metastatic melanoma. Patients were randomized to receive either oral PLX4032 twice daily, or the current standard of care, which consists of intravenous dacarbazine every three weeks.
Plexxikon CEO Peter Hirth declined to give any more details about the magnitude of either survival benefit, or the response rate. But, he told BioWorld Today, the data were so strong that the study was terminated early, and patients in the control arm have been given the option to cross over onto PLX4032. In that sense, he said, "the study is done," because trying to gauge differences once there is such a crossover option "would lead the overall survival [measurements] ad absurdum.
"However," he added, "we are still following the patients from a safety perspective."
Based on the data, the company plans to file for regulatory approval for PLX4032 in 2011, Plexxikon President Kathy Glaub told BioWorld Today.
With that, the company may just be breaking a land speed record. The Phase I trial of PLX4032 began in December 2006. The results of that trial, which were published in 2010, prompted the drug's developers, Berkeley, Calif.-based Plexxikon and partner Roche AG, to move the drug directly into pivotal testing. The first patient was enrolled in the BRIM3 study in January 2010.
"We will probably see more of this [rapid clinical progress] with other personalized drugs," Glaub said. PLX4032, she added, is "a highly personalized drug and as a result, we're really forging some new pathways, even in the regulatory area."
PLX4032, an orally active kinase inhibitor that targets an activating BRAF mutation, is also an example of the power of personalized medicine. The drug is being co-developed with a diagnostic test to identify patients whose tumors carry the V600 mutation. Such mutations account for about half of all melanoma cases.
The extremely rapid hurtle down the clinical development path also means that the conclusions about PLX4032's safety and efficacy are based on relatively few patients, and relatively few clinical events. Such small numbers and statistics can be shaky, but both Hirth and Glaub said that because of the strength of the data, they are not concerned that the sample size is small.
"We're not worried, because we've seen such consistent data that it has really been very clear," Glaub said. And because PLX4032 is undergoing "a very exceptional development paradigm," which was characterized from the beginning by testing the drug only in a molecularly targeted population, the trials were designed to get a lot of information. "In a way, our Phase I trial produced data that are usually what you get in Phase II."
Finally, Hirth added, "the more impact a drug has, the easier it is to see [effects]. . . . This is all a testament to the power of the drug."
With response rates of up to 80 percent reported in early stage trials, PLX4032 is something of a wonder drug in the cancer field, where drugs can be approved and considered successes with response rates of well below 25 percent.
But there had been concern that even such stellar response rates might not translate into improved survival.
Drug developers and patients alike have been disappointed before targeted cancer drug Iressa (gefitinib, AstraZeneca plc), for example, received fast-track approval in 2003 on the basis of response rate, but subsequently its indications were severely curtailed when a Phase IV study failed to show a survival benefit for patients taking the drug. (See BioWorld Today, May 6, 2003, and Dec. 20, 2004.)
At 10 percent, the response rate to Iressa was far lower than that to PLX4032. But worries about survival were also fueled by another statistic about PLX4032: More than half of the patients in one trial developed resistance to the drug within less than a year, apparently via a multitude of mechanisms. (See BioWorld Today, Nov. 29, 2010.)
The increase in overall and progression-free survival, which were the co-primary endpoints of the BRIM3 trial, lay those worries to rest.
Hirth said that precisely because the BRIM3 trial ended so quickly, the interim analysis doesn't have any information about resistance yet. "In that early readout, we would not see anything" that could tell the company what the long-term resistance rate might be.
But, he added, "we have been actively working on [resistance] . . . and we think we've had a major breakthrough. We are working on a best-in-class agent that will hopefully not have this resistance issue." The company also plans to share more details about that scientific advance at a medical conference in 2011.