The vast majority of patients with advanced, metastatic melanoma gain only a few months extra survival from standard treatment. But early tests show that an experimental drug, dubbed PLX4032 by Plexxikon and Roche Pharmaceuticals, offers far greater benefits.
The findings are particularly amazing as they come from a very early, phase I clinical trial. Study leader Keith T. Flaherty, MD, is director of developmental therapeutics at Massachusetts General Hospital.
"For those who respond to treatment, the average duration of progression-free survival is nine months," Flaherty tells WebMD. "Some patients are over a year and a half and cruising to two years. In melanoma, that is good. ... The average time for standard treatment is two months."
There is a catch. The drug targets a specific genetic mutation that helps melanoma tumor cells grow. Some 40% to 60% of melanoma patients have tumors with this mutation.
For those who don't, the drug offers no help and possible harm. Fortunately, a simple genetic test identifies patients likely to respond to the drug.
In its initial phase, the study enrolled 55 patients, 49 with metastatic melanoma. An additional 32 patients with metastatic melanoma enrolled in the study's extension phase. All patients carried the BRAF mutation targeted by the new drug.
The result: 81% of patients with BRAF-positive melanoma responded to treatment. Duration of response ranged from two to over 18 months. Three of the melanoma patients no longer had detectable tumor in their bodies, although Flaherty says such "complete responses" are not the same as cures.
"These results represent a major breakthrough," write Keiran S.M. Smalley, PhD, and Vernon K. Sondak, MD, of Tampa's Moffitt Cancer Center in an editorial that accompanies the Flaherty team's report in the Aug. 26 issue of the New England Journal of Medicine. Smalley and Sondak were not involved in the Flaherty study.
The drug "seems to be extremely effective and causes a very high response rate that happens pretty quickly," Sondak tells WebMD. "It can cause improvement even in people who failed standard treatments. It shows a benefit even in patients with tumors in their livers and other places where traditional treatment bogs down a lot."
New Melanoma Drug: Making It Better
Yes, the drug -- a pill taken twice daily -- has side effects. The most common ones are a rash, sun sensitivity, joint discomfort, and fatigue. A number of patients also developed non-deadly squamous-cell carcinomas on the skin. Flaherty says these side effects tend to be moderate and manageable -- and that patients have a good quality of life while on therapy.
The drug's most important drawback is that it isn't a cure. Eventually, tumor cells find new ways to grow and become resistant to the new drug.
"Nine months extra progression-free survival is not what patients come to us for," Flaherty says. "But we think there are ways to make it better."
"While we need a lot of research, there are many achievable ways to combat that resistance," Sondak says. "Once we understand it a little better and develop new drug combinations, we can keep moving the bar and get responses in more people that last longer and longer. Maybe, eventually, even to the point where we cured this person."
New Melanoma Drug: Turning Point for Cancer Research?
Sondak says that the new drug's success has huge implications for the entire field of cancer research.
"What I think is exciting is the broad perspective: Melanoma isn't the only cancer with this mutation, just the one where it is most common," he says. "And what's really good news is the success of this idea that you can target a cancer gene and do something good. Now we can start looking for similar mutations in other genes important in other cancers. We now have another proof that this is a fertile line of research."
Today's exciting results come just eight years after the first genetic study found that the BRAF mutation is important for tumor growth.
"So in a very short time, from discovery of the mutation to publication of the Flaherty trial results, we went through all those individual steps and went very, very quickly to a point where everyone could see we had a drug with much better responses than any other melanoma treatment," Sondak says. "To me that is the excitement. It shows the cancer research we are doing is paying off."
What Should Today's Melanoma Patients Do?
Despite all this excitement, the reality is that PLX4032 is not yet ready for prime time. A phase III clinical trial is now enrolling patients with BRAF-positive tumors. In that trial, some patients will get the drug (in a version dubbed RO5185426) and others will get standard treatment.
Only after this trial is completed and analyzed will it be known whether the drug truly works -- and only then will it be available to patients.
There's a bit more good news for the future. A similar drug from GlaxoSmithKline, called GSK2118436, is enrolling patients in a phase II study.
"The bottom line is that if I were a patient, I would be looking for either one in a clinical trial," Flaherty says.
Another big question is what the new drug might mean for patients with early-stage melanoma. Stage I tumors can be cured with surgery. But melanoma is infamous for how quickly it can spread through the body from a small skin tumor. About half of patients with metastatic melanoma had previously had apparently curative melanoma surgery.
It's not at all clear whether giving one of the new BRAF inhibitors to such patients would keep their cancers from coming back.
"Getting to the clinical trial evaluation of this is urgent and we are getting that under way," Flaherty says. "We don't know if eradicating microscopic cancer cells is the same trick as beating down large tumors. But with two other targeted therapies, Gleevec and Herceptin, it does appear that they truly can prevent recurrences. We are just as hopeful for this drug."