Fantastic and “the next big thing” were how two of the principal investigators described the results of an interim analysis of the phase III trial of PLX4032, the harbinger of a significant breakthrough in the treatment of metastatic melanoma.
PLX4032 works by inhibiting a protein produced by a gene mutation in melanoma cells. In phase I and II trials, many of the patients whose tumor cells manifested the BRAF V600 mutation responded to the drug with tumor shrinkage that lasted for an average of 6 months.
Now, a controlled phase III trial pitting PLX4032 against dacarbazine showed that patients who received the investigational drug had a significant survival advantage, as well as increased time to disease progression when compared to standard therapy.
How much extra survival? “We don’t know the answer to that yet,” said Keith Flaherty, MD, Director of Developmental Therapeutics, Massachusetts General Hospital Cancer Center, and one of the principal investigators for the study. The data will be presented at the ASCO Annual Meeting.
Melanoma Treatments Not Effective
Dacarbazine’s response rate in metastatic melanoma is 10% to 15%. In the prior phase I and II trials, more than 50% of the patients with melanoma who had the BRAF mutation responded to PLX4032.
“We knew going into the phase III trial that the response rate to PLX4032 would be higher than to dacarbazine. We also knew that these responses were typically not long-lasting. The average duration of response observed in earlier studies suggested but did not prove that survival would be improved for PLX4032,” said Dr. Flaherty. Hence, a study with survival as the primary endpoint was clearly needed.
Dr. Flaherty also noted that dacarbazine was approved more than 30 years ago. If it had been submitted for approval in today’s more stringent regulatory environment, it would not have made the grade, he speculated.
Prior to 2011, only two drugs (dacarbazine and high-dose interleukin-2 [Proleukin]) had been approved for treating metastatic melanoma, and neither one of these results in acceptable survival. A third, ipilimumab (Yervoy), was recently approved by FDA on March 25, 2011. Ipilimumab is a monoclonal antibody that inhibits the cytotoxic T lymphocyte–associated antigen 4 (CTLA-4). Several phase II studies have shown that ipilumumab can provide 1-year survival rates of nearly 50%. Ipilimumab has been associated with potentially life-threatening toxicity, including gastrointestinal perforation and sepsis.
In June 2010, The New England Journal of Medicine published a report1 of a phase III study of 676 patients with stage III or IV melanoma (which was initially presented at the Plenary Session of the 2010 ASCO Annual Meeting). They were randomly assigned to receive ipilimumab plus a glycoprotein 100 peptide vaccine (gp100), ipilimumab alone, or gp100 alone. Median overall survival was significantly better in patients who received either the combination or ipilimumab alone (10 and 10.1 months, respectively) compared to those on gp100 alone (6.4 months). However, it should be noted that 14 deaths were related to study drugs.
The Present Trial
The BRIM3 trial, sponsored by Roche and Plexxikon, a biotech company in Berkeley, California, was begun in January 2010 with 675 patients with previously untreated melanoma who had the BRAF V600 mutation. (It was stopped only a year later—the shortest phase III trial on record.) It was randomized, controlled, open-label, and multinational, with the primary endpoint of overall survival and secondary endpoints of time to disease progression and duration of response. Half the patients were given dacarbazine and half were given PLX4032. Patients continued on the study until disease progression or until unacceptable toxicity.
Although the final results from BRIM3 are currently unknown, in a phase I trial PLX4032 provided an average remission of approximately 7 months from initiation of treatment. The longest responders have been taking the drug for 2 years. Paul Chapman, MD, Attending Physician in the Melanoma-Sarcoma Services Department, Memorial Sloan-Kettering Cancer Center, said “This is the first-ever drug for melanoma that correlates improved survival with improved response rate. We had hoped this would happen, but we didn’t know until we did the trial.”
Adverse events for PLX4032 included keratoacanthoma, a relatively common, benign skin lesion, increases in liver enzymes, rash, photosensitivity, joint pain, hair loss, and fatigue.
Dr. Flaherty believes that PLX4032 will receive accelerated approval this year or early in 2012. This is the “next big thing,” he said, and until it is improved upon, it will become the standard treatment for metastatic melanoma.
Dr. Chapman agreed. “It’s fantastic. Now we have something solid to build on. For the first time, we know the mechanism of action of a drug that improves survival, and although single-drug treatments are never the most effective, PLX4032 has given us a huge leg up in the search for a successful combination.”
The Genetics of Melanoma
Metastatic melanoma is associated with an average life expectancy of 8 months after diagnosis. Not only are there few treatment options, there has been no significant improvement in treatment for 30 years. Moreover, the incidence is expected to double over the next decade.
About half of the 68,000 people diagnosed every year have the BRAF mutation, which results in increased cell proliferation and apoptosis. PLX4032 is designed to selectively inhibit the mutated form of the BRAF protein and has been shown to significantly delay growth in tumors harboring the BRAF V600 mutation.
However, PLX4032 is not exempt from inevitable drug resistance. “Everyone develops resistance sooner or later,” said Dr. Flaherty.
There might be a secondary mutation in the BRAF gene that prevents binding, but resistance can occur even in its absence. “Preliminary analyses of tumors collected from patients whose disease has progressed suggest something other than mutations in BRAF. It may be other mutations and/or signal transduction alterations or activation of a parallel signal pathway,” said Dr. Flaherty.
Meenhard Herlyn, DVM, DSc, Leader, Molecular and Cellular Oncogenesis Program, Wistar Institute, and his Wistar colleague, Jessie Villanueva, PhD, Staff Scientist, noted that even if inhibition of mutant BRAF shuts down a major pathway, some cancer cells can use an alternate pathway and survive.2 Thus, resistant cells can reroute their signal around BRAF by switching to an alternate protein that promotes tumor cell growth.
Combination therapies may overcome resistance. Drs. Herlyn and Villanueva have developed a model that allows melanoma cells to grow in vitro to determine which are vulnerable to various drug combinations. They also found that tissue samples taken from patients in phase I and phase II trials both before treatment and after they developed resistance show that an increased expression of one particular receptor is associated with resistance to BRAF inhibitors. And they noted an association between the loss of the tumor suppressor PTEN and resistance to BRAF inhibitors in melanoma cell lines. In fact, the relapsed tumor of one patient lost the PTEN gene even though it was present before treatment, suggesting that loss of PTEN could be an additional path to resistance.
“BRAF mutations are probably necessary—but insufficient—to turn a cell into a melanoma,” Dr. Chapman added. “There are still a lot of unknowns—for instance, why some patients with the BRAF mutation responded to PLX4032 and some didn’t. But, we are racing to understand the mechanism of resistance and find other agents to combine with PLX4032.”
Drs. Flaherty and Chapman agreed that all patients with melanoma should be tested for the BRAF mutation and other genetic characteristics at diagnosis, preferably as part of the original pathologic examination. To that end, a number of diagnostic tests have been developed, one of which is Roche’s cobas 4800 BRAF V600 Mutation Test.
What’s Next for PLX4032?
Dr. Flaherty believes that PLX4032 has “blown the door off” the barriers to therapeutic response to a melanoma drug. “PLX4032 will be used as a stepping stone to more trials with a variety of drug combinations, some perhaps with other MAP kinase pathway inhibitors and some with compounds that affect other mutated pathways.”
PLX4032 is available through an expanded-access program from Roche, since the drug is currently investigational and not FDA approved. Dr. Flaherty is a proponent of this and other expanded-access programs.
“We’re in the business of finding drugs to treat people, and when we find one, they should be given access,” he said, but that doesn’t mean that patients with cancer should have access to any compound that comes down the pike. “It’s preposterous to give people an unproven drug. That’s the road back to the bad old snake oil days. But if there’s a drug that works and is on its way to approval, then of course, patients should have it.” ■
Financial Disclosure: Dr. Chapman reports serving as a consultant for Roche Pharmaceuticals. Dr. Flaherty reports serving as a consultant for GlaxoSmithKline and Roche Pharmaceuticals. Dr. Herlyn reported no potential conflict of interest. Dr. Turnham is an employee of the Melanoma Research Foundation. Dr. Villanueva reported no potential conflict of interest.
Reference
1. Hodi FS, O’Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-723, 2010.
2. Villanueva J, Vultur A, Lee JT, et al: Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18:683-695, 2010.
